Fsh receptor antagonists

ABSTRACT

The invention relates to FSH receptor antagonist according to general formula (I) or a pharmaceutically acceptable salt thereof and to a pharmaceutical composition containing the same. The compounds can be used for the treatment and prevention of endometriosis, for the treatment and prevention of pre-menopausal and peri-menopausal hormone-dependent breast cancer, for contraception, and for the treatment of uterine fibroids and other menstrual-related disorders.

The invention relates to a compound having FSH receptor modulatoryactivity, to a pharmaceutical composition containing the same, as wellas the use of said compound for FSH receptor mediated diseases.

Gonadotropins are important in a variety of bodily functions includingmetabolism, temperature regulation and the reproductive process.Gonadotropins act on specific gonadal cell types to initiate ovarian andtesticular differentiation and steroidogenesis. The hypophysealgonadotropin FSH (follicle stimulating hormone) for example is releasedfrom the anterior pituitary under the influence ofgonadotropin-releasing hormone and estrogens and plays a pivotal role inthe stimulation of follicle development and maturation. FSH is the majorhormone regulating secretion of follicular estrogens, whereas LH(luteinizing hormone) stimulates the production of folliculartestosterone and induces ovulation (Sharp, R. M. Clin Endocrinol.33:787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res.35:301-342, 1979).

The actions of the FSH hormone are mediated by a specific plasmamembrane receptor that is a member of the large family of G-proteincoupled receptors. These receptors consist of a single polypeptide withseven transmembrane domains and are able to interact with the Gsprotein, leading e.g. to the activation of adenylate cyclase.

The FSH receptor (FSHR) is a highly specific target in the ovarianfollicle growth process and is exclusively expressed in the ovary.Blocking this receptor or inhibiting the signaling which is normallyinduced after FSH-mediated receptor activation will disturb follicledevelopment and thus production of estrogens, ovulation and fertility.Low molecular weight FSH receptor antagonists, henceforth termed FSHRantagonists, could therefore form the basis for medical therapies thatare in need of diminished production of estrogens and/or induction ofanovulation.

Low molecular weight FSH receptor antagonists have been disclosed inInternational Applications WO 2008071455, WO 200807145 and WO 2008117175and in van Straten, N. C. R. and Timmers, C. M. Annual Reports inMedicinal Chemistry 44:171-188, 2009 and van Straten, N. C. R. et al J.Med. Chem. 48:1697-1700, 2005.

Preventing or reversing endometriosis is an important goal in the fieldof women's health care. Endometriosis is a painful gynecologicalcondition that is characterized by the presence of endometrial tissue insites outside of the uterine cavity. The prevalence rate isapproximately 10% but this may be an underestimate because of the needto perform a laparoscopic procedure to determine the presence ofdisease. The disease affects women of reproductive age, the most commonsymptoms being painful menstruation (dysmenorrhoea), pain duringintercourse (dyspareunia), painful bowel movement (dyschezia), chronicpelvic pain, heavy periods (menorrhagia), and infertility. If leftuntreated or inadequately treated endometriosis can either progress orspontaneously regress. In a significant number of women endometriosis isa chronic progressive disease manifesting itself as intractable pain,worsening quality of life, and infertility.

The etiology is unclear which also hampers an understanding of thesymptomatic implications of the disease. Endometriosis produces an arrayof symptoms of varying severity with lack of correlation between stageof disease, disease load and degree of pain thereby causing confusionwith clinical classification and delay in diagnosis. Known treatmentoptions are drug therapy and conservative surgery.

Drug therapy is with analgesics, hormonal contraceptives which containboth estrogen and progestagen (Combined Oral Contraceptive (COC)) orprogestagen only (Progestagen-Only Contraceptive (POC)), gonadotropinreleasing hormone (GnRH) agonists, or other hormones e.g. danazol. Oralcontraceptive regimens with combined use of an estrogen and aprogestagen (COC) are widely used as first-line therapy in suspected ordiagnosed endometriosis, owing to their property to provide cyclecontrol, reduce menstrual flow and eradicate dysmenorrhoea, the mostcommon symptom especially in early-stage disease. However, no singleproduct offers sufficient efficacy in combination with a tolerable levelof side effects. COCs may treat some of the symptoms well, but do noteffectively suppress the progress of endometriosis and do noteffectively treat chronic pelvic pain.

COCs produce initial decidualization of the endometrium by creating astate of pseudocyesis and later atrophy and thinning of the endometrium,thereby providing cycle control, reduction in menstrual flow andreduction of dysmenorrhoea. COCs may treat thereforemenstruation-related symptoms but they do not completely suppress thegrowth of endometriotic lesions and associated chronic pelvic pain.

The mechanism of action of progestagens is initial decidualization ofendometrium, followed by atrophy as a result of a direct suppressiveeffect on estrogen receptors in the endometrium. There is evidence thatprogestagens suppress matrix metalloproteinases at the molecular levelthereby inhibiting the growth of ectopic endometrium.Medroxyprogesterone acetate is the most widely used progestagen for thetreatment of endometriosis. Although available for oral administration,medroxyprogesterone acetate is usually administered as a depotformulation every 3 months. The side effects of POCs are multiple, themost common being breakthrough bleeding, nausea, fluid retention andbreast tenderness.

GnRH agonists and GnRH antagonists down-regulate theHypothalamus-Pituitary-Ovary axis by downregulation of the GnRH receptorand GnRH receptor-mediated signalling, resulting in a hypo-estrogenicmenopausal state, endometrial atrophy, and amenorrhoea. Although veryeffective in reducing circulating levels of estrogens, multiple sideeffects related to menopausal symptoms as well as osteoporosis limitduration of treatment with GnRH agonists to 6 months. Known drugtreatments and/or conservative surgery offer temporary relief only andrelapse rates can be as high as 50% with a major impact on fertility andquality of life. Moreover, a significant number of women aged 40-44years require hysterectomy and bilateral salpingo-oophorectomy.

There is thus a strong need for early therapeutic intervention thatimproves on the above-mentioned shortcomings of available treatmentoptions. The need is in particular for early therapeutic interventionthat suppresses progression of disease and/or improves the side-effectprofile (i.e. unscheduled bleeding, bone loss and menopausal symptoms)and improves fertility outcomes.

The present invention therefore relates to FSHR antagonists as a meansfor the treatment and prevention of endometriosis, for the treatment andprevention of pre-menopausal and peri-menopausal hormone-dependentbreast cancer, for contraception, and for the treatment of uterinefibroids and other menstrual-related disorders, such as dysfunctionaluterine bleeding.

The present invention provides compounds having the general Formula I ora pharmaceutically acceptable salt thereof.

In this Formula X, Y, R3, and R7, R8, R9, R13, R14 and R15 have thefollowing definitions:

X is C(R10) or N;

Y is C(R1) or N;

R1 is H, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl;

R3 is phenyl, (2-8C)-heteroaryl, benzoyl, (2-8C)heteroarylcarbonyl, thephenyl or heteroaryl moieties of which may optionally be substitutedwith one or more substituents selected from R11, or

R3 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl,(1-6C)alkylcarbonyl, (2-6C)alkenylcarbonyl, (2-6C)alkynylcarbonyl or(3-6C)cycloalkylcarbonyl;

R7 and R8 are independently H or (1-4C)alkoxy;

R9 is hydroxy or H, or

R9 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-4C)alkoxy,(2-4C)alkenoxy, (3-6C)cycloalkyl, (3-6)cycloalkoxy,(3-6C)cycloalkyl(1-4C)alkoxy, (2-6C)heterocycloalkylcarbonyl,(di)[1-4C]alkylaminocarbonyl,

(2-6C)heterocycloalkyl, the alkyl or (hetero)cycloalkyl moieties ofwhich may optionally be substituted with one or more substituentsselected from R12 or,

R9 is (2-8C)heteroaryl, phenyl, phenyl(1-4C)alkoxy,(2-8C)heteroaryl(1-4C)alkoxy, the phenyl or heteroaryl moieties of whichmay optionally be substituted with one or more substituents selectedfrom R16;

R10 is H or (1-4C)alkoxy;

R11 is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano,(1-4C)alkyl, (1-4C)alkoxy or (di)[1-4C)alkyl]amino;

R12 is hydroxy, amino, halogen, cyano, (1-4C)alkoxy or(di)[1-4C)alkyl]amino;

R13 and R14 are independently H or (1-3C)alkyl;

R15 is H, (1-3C)alkyl, or

R14 and R15 may be joined in a (3-6C)cycloalkyl ring; and

R16 is hydroxy, amino, halogen, nitro, trifluoromethyl, cyano,(1-4C)alkyl, (1-4C)alkoxy or (di)[1-4C)alkyl]amino.

The compounds according to the present invention have FSHR modulatoryactivity and dose titration with such FSHR antagonists give rise todiminished follicle development (no ovulation) and reduction ofcirculating levels of estrogens with still sufficient estrogenproduction left to avoid adverse effects on e.g. bone mass.

Without intending to be bound by theory, the compounds according to thepresent invention are able to provide optimal control over circulatinglevels of estrogens by the fact that the compounds are allosteric FSHRantagonists and will therefore be less sensitive to an increase incirculating levels of FSH due to a loss of feedback inhibition bydecreased levels of circulating estrogens. Moreover, dose titration ofthe FSHR antagonist would allow for a second level of control over FSHRsignalling and thus over the balance between efficacy (decrease inestrogens) and side effects (minimal level of residual estrogens).

In contrast to GnRHR (ant)agonist treatment regimens, the highertolerability of FSHR antagonists enables treatment for periods exceeding6 months.

The term (1-3C)alkyl as used here above means a branched or unbranchedalkyl group having 1-3 carbon atoms, being methyl, ethyl, propyl andisopropyl.

The term (1-4C)alkyl means a branched or unbranched alkyl group having1-4 carbon atoms, being methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl.

The term (1-6C)alkyl means a branched or unbranched alkyl group having1-6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, n-pentyl and n-hexyl. (1-5C)Alkyl groups are preferred,(1-4C)alkyl being the most preferred.

The term (1-4C)alkoxy means an alkoxy group having 1-4 carbon atoms, thealkyl moiety having the same meaning as previously defined. (1-3C)Alkoxygroups are preferred.

The term (1-6C)alkylcarbonyl means an alkylcarbonyl group, the alkylgroup of which contains 1-6 carbon atoms with the same meaning aspreviously defined.

The term (2-4C)alkenyl means a branched or unbranched alkenyl grouphaving 2-4 carbon atoms, such as ethenyl, propenyl and 2-butenyl.

The term (2-6C)alkenyl means a branched or unbranched alkenyl grouphaving 2-6 carbon atoms, such as ethenyl, 2-butenyl, and n-pentenyl.

The term (2-6C)alkenylcarbonyl means an alkenylcarbonyl group, thealkenyl group of which contains 2-6 carbon atoms with the same meaningas previously defined.

The term (2-4C)alkenoxy means an alkenoxy group, the alkenyl group ofwhich contains 2-4 carbon atoms with the same meaning as previouslydefined.

The term (2-4C)alkynyl means a branched or unbranched alkynyl grouphaving 2-4 carbon atoms, such as ethynyl, propynyl and butynyl.

The term (2-6C)alkynyl means a branched or unbranched alkynyl grouphaving 2-6 carbon atoms, such as ethynyl, propynyl and n-pentynyl.

The term (2-6C)alkynylcarbonyl means an alkynylcarbonyl group, thealkynyl group of which contains 2-6 carbon atoms with the same meaningas previously defined.

The term (3-6C)cycloalkyl means a cycloalkyl group having 3-6 carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term (3-6C)cycloalkylcarbonyl means a cycloalkylcarbonyl group, thecycloalkyl group of which contains 3-6 carbon atoms with the samemeaning as previously defined.

The term (3-6C)cycloalkoxy means a cycloalkoxy group having 3-6 carbonatoms, such as cyclopropoxy, cyclobutoxy and cyclopentoxy.

The term (3-6C)cycloalkyl(1-4C)alkoxy means a cycloalkylalkoxy group,the cycloalkyl group of which contains 3-6 carbon atoms with the samemeaning as previously defined and the alkoxy group of which contains 1-4carbon atoms with the same meaning as previously defined.

The term (2-6C)heterocycloalkyl means a heterocycloalkyl group having2-6 carbon atoms, preferably 3-5 carbon atoms, including 1-3 heteroatomsselected from N, O and/or S, which may be attached via a nitrogen iffeasible, or a carbon atom. Preferred heteroatoms are N or O. Preferrednumber of heteroatoms is one or two. Most preferred are piperidin-1-yl,morpholin-4-yl, pyrrolidin-1-yl and piperazin-1-yl.

The term (2-8C)heteroaryl means an aromatic group having 2-8 carbonatoms and 1-4 heteroatoms selected from N, O and S, like imidazolyl,thiadiazolyl, pyridinyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, furylor indolyl. Preferred number of heteroatoms is one or two. Preferredheteroaryl groups are thienyl, oxazolyl, imidazolyl, pyrazolyl,pyrimidinyl, pyrazinyl, furyl and pyridinyl. Most preferred are thienyl,furyl and pyridinyl. The (2-8C)heteroaryl group may be attached via acarbon atom or a nitrogen, if feasible.

The term (di)[(1-4C)alkyl]amino as used herein means an amino group,monosubstituted or disubstituted with alkyl group(s), each containing1-4 carbon atoms and having the same meaning as previously defined.

The term (di)[(1-4C)alkyl]aminocarbonyl means a (di)alkylaminocarbonylgroup, the alkyl group(s) of which each contain(s) 1-4 carbon atoms withthe same meaning as previously defined.

The term phenyl(1-4C)alkoxy means a phenylalkoxy group, the alkoxy groupof which contains 1-4 carbon atoms with the same meaning as previouslydefined.

The term (2-8C)heteroaryl(1-4C)alkoxy means a heteroarylalkoxy group,the heteroaryl group of which contains 2-8 carbon atoms with the samemeaning as previously defined and the alkoxy group of which contains 1-4carbon atoms with the same meaning as previously defined.

The term (2-8C)heteroarylcarbonyl means a heteroarylcarbonyl group, theheteroaryl group of which contains 2-8 carbon atoms with the samemeaning as previously defined.

The term (2-6C)heterocycloalkylcarbonyl means a heterocycloalkylcarbonylgroup, the heterocycloalkyl group of which contains 2-6 carbon atomswith the same meaning as previously defined.

The term halogen means fluorine, chlorine, bromine or iodine.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

In the above definitions with multifunctional groups the attachmentpoint is at the last group. The term pharmaceutically acceptable saltrepresents those salts which are, within the scope of medical judgement,suitable for use in contact for the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. They may be obtained duringthe final isolation and purification of the compounds of the invention,or separately by reacting the free base function with a suitable mineralacid such as hydrochloric acid, phosphoric acid, or sulfuric acid, orwith an organic acid such as for example ascorbic acid, citric acid,tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid,glycolic acid, succinic acid, propionic acid, acetic acid,methanesulfonic acid, and the like. The acid function can be reactedwith an organic or a mineral base, like sodium hydroxide, potassiumhydroxide or lithium hydroxide.

In one aspect the invention relates to compounds according to Formula Iwherein R1 is H or (1-4C)alkyl; R8 is (1-4C)alkoxy; R9 is hydroxy or R9is (1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy, (2-4C)alkenoxy,(3-6)cycloalkoxy, (3-6C)cycloalkyl(1-4C)alkoxy,(2-6C)heterocycloalkylcarbonyl, (di)[1-4C]alkylaminocarbonyl, the alkylor (hetero)cycloalkyl moieties of which may optionally be substitutedwith one or more substituents selected from R16 or R9 is(2-8C)heteroaryl, phenyl(1-4C)alkoxy, the phenyl or heteroaryl moietiesof which may optionally be substituted with one or more substituentsselected from R11.

In another aspect the invention relates to compounds according toFormula I wherein Y is C(R1).

In yet another aspect the invention relates to compounds according toFormula I wherein R1 is H.

In another aspect the invention relates to compounds according toFormula I wherein R13, R14 and R15 are H.

The invention also relates to compounds according to Formula I whereinR9 is (1-6C)alkyl, (1-4C)alkoxy or (3-6C)cycloalkyl(1-4C)alkoxy. Thealkyl moieties of these groups may optionally be substituted with one ormore substituents selected from R12. R9 might also be (2-8C)heteroarylor phenyl(1-4C)alkoxy, the phenyl or heteroaryl moieties of which mayoptionally be substituted with one or more substituents selected fromR11.

In a further aspect the invention relates to compounds according toFormula I wherein R3 is phenyl, (2-8C)-heteroaryl, benzoyl,(2-8C)heteroarylcarbonyl. The phenyl or heteroaryl moieties mayoptionally be substituted with one or more substituents selected fromR11, R3 might also be (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkylcarbonyl or(3-6C)cycloalkylcarbonyl.

In still another aspect the invention resides in compounds according toFormula I wherein R3 is phenyl or (2-8C)-heteroaryl, both optionallysubstituted with one or more substituents selected from R11.

In another aspect the invention resides in compounds according toFormula I wherein X is C(R10).

The invention also relates to compounds according to Formula I whereinthe optional substituent R11 in R3 is hydroxy, amino, halogen, nitro,trifluoromethyl, cyano, (1-4C)alkyl or (1-4C)alkoxy.

The invention also relates to compounds according to Formula I whereinthe optional substituent R12 in R9 is hydroxy, (1-4C)alkoxy or(di)[1-4C)alkyl]amino.

The invention also relates to compounds according to Formula I whereinthe optional substituent R16 in R9 is (1-4C)alkyl, (1-4C)alkoxy or(di)[1-4C)alkyl]amino.

The invention also relates to those compounds wherein all specificationsfor X, Y, R1, R3 and R7 through R16 in the various aspects of theinvention as described hereabove occur in any combination within thedefinition of the compound according to Formula I.

In another aspect the invention relates to compounds of Formula I whichhave a pIC50 of 5 or higher. In yet another aspect the invention relatesto compounds according to Formula I with a pIC50 of more than 7.

In yet another aspect the invention resides in the compounds accordingto Formula I selected described in examples 1-71.

The skilled artisan will recognize that desirable IC50 values aredependent on the compound tested. For example, a compound with an IC50value which is less than 10⁻⁵M is generally considered a candidate fordrug selection. Preferably, this value is lower than 10⁻⁷M. However, acompound which has a higher IC50 value, but is selective for theparticular receptor, may be even a better candidate.

In vitro assays to determine receptor binding or the biological activityof gonadotropin receptor agonists and antagonists are well-known. Ingeneral, cells expressing the receptor are incubated with the compoundto be tested and the binding or stimulation or inhibition of afunctional response is determined. To measure a functional response,isolated DNA encoding the FSH receptor gene, preferably the humanreceptor, is expressed in a suitable host cell-line. Such a hostcell-line might be the Chinese Hamster Ovary cell-line, but othercell-lines can also be used. Preferably, the host cells are of mammalianorigin (Jia et al (1991) Mol Endocrinol 5, 759-776).

Methods to construct FSH receptor-expressing cell lines are well-knownin the art (e.g., Sambrook et al., Molecular Cloning: A LaboratoryManual, Cold Spring Harbor Laboratory Press, latest edition).Heterogolous expression of the receptor is obtained by transfection andexpression of the DNA encoding the desired protein. Techniques forsite-directed mutagenesis, ligation of additional sequences, PCR, andconstruction of suitable expression systems are also well-known in theart. Portions, or all, of the DNA encoding the desired protein can beconstructed synthetically using standard solid phase techniques,preferably to include restriction sites for ease of ligation. Suitablecontrol elements for transcription and translation of the includedcoding sequence can be provided to the DNA coding sequences. As iswell-known, expression systems are available, which are compatible witha wide variety of hosts, including prokaryotic hosts such as bacteriaand eukaryotic hosts such as yeast, plant cells, insect cells, aviancells, mammalian cells, and the like.

Cells expressing the receptor are then incubated with the test compoundto determine binding, or stimulation or inhibition of a functionalresponse. Alternatively, isolated cell membranes containing theexpressed receptor may be used to measure binding of compound.

For measurement of binding, radioactively- or fluorescently-labeledcompounds may be used. Alternatively, competition binding assays may beperformed. FSH receptor antagonistic compounds can also be identified inscreening assays that involve the determination of receptor-mediatedcAMP accumulation. Such methods involve the expression of the FSHreceptor in a host cell-line and incubation of the cells with aconcentration range of the test compound in the presence of a fixed,submaximally effective, FSH concentration (i.e., a FSH concentrationthat induces approximately 80% of the maximal cAMP accumulation by FSHin the absence of test compound). The amount of cAMP is then measured.From the concentration-effect curves, the IC50 value and the percentageof inhibition of FSH-induced cAMP accumulation can be determined foreach of the compounds. As agonist, human recombinant FSH can be used.

In addition to the direct measurement of cAMP levels in the FSHreceptor-expressing cell-line, cell-lines may be transfected with asecond cDNA that encodes a reporter gene, of which the expression isdependent on the intracellular concentration of cAMP. Such reportergenes might be cAMP-inducible or be constructed in such a way that theyare connected to novel cAMP responsive elements. In general, reportergene expression might be controlled by any response element reacting tochanging levels of intracellular cAMP. Suitable reporter genes are e.g.the genes encoding beta-galactosidase, alkaline phosphatase, fireflyluciferase and green fluorescence protein. The principles of suchtransactivation assays are well-known in the art and are described forexample in Stratowa et al (1995) Curr Opin Biotechnol 6, 574. Changes inintracellular cAMP levels may also be determined in live-cell cAMPbiosensor assays, like the GloSensor™ cAMP assay, which uses agenetically encoded biosensor with a cAMP binding domain fused to amutant form of luciferase, or the ACT One™ cAMP assay, which utilizes acAMP-gated ion channel as a biosensor. Antagonistic compounds may alsobe identified in assays that are based on receptor-induced recruitmentof beta-arrestin to the agonist-occupied receptor (e.g., Transfluor®assay, PathHunter® and Tango™ beta-arrestin assays) or receptorinternalization assays (e.g., Path Hunter® endocytosis assays).Label-free assays may also be applicable to screen for FSH receptorantagonists. These assays are based on receptor-induced dynamic massredistribution of intracellular content or receptor-induced changes incell morphology or adhesion (Van Koppen (2010) Drug Discovery tb 7, 69).

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated.

The compounds of Formula I may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g. hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula I may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers. Individual stereoisomers of the compounds of the invention may,for example, be substantially free of other isomers, or may be admixed,for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations.

The compounds of the invention may form hydrates or solvates. It isknown to those of skill in the art that charged compounds form hydratedspecies when lyophilized with water, or form solvated species whenconcentrated in a solution with an appropriate organic solvent. Thecompounds of this invention include the prodrugs, hydrates or solvatesof the compounds.

A discussion of prodrugs is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. SymposiumSeries, and in Bioreversible Carriers in Drug Design, (1987) Edward B.Roche, ed., American Pharmaceutical Association and Pergamon Press andJana S. et al, Current Med. Chem. 17, 3874-3908, 2010. The term“prodrug” means a compound (e.g, a drug precursor) that is transformedin vivo to yield a compound of Formula I or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound. The transformationmay occur by various mechanisms (e.g. by metabolic or chemicalprocesses), such as, for example, through hydrolysis in blood. Adiscussion of the use of prodrugs is provided by T. Higuchi and W.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like,is intended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also relates to a pharmaceutical compositioncomprising compounds or pharmaceutically acceptable salts thereof havingthe general formula I in admixture with pharmaceutically acceptableauxiliaries and optionally other therapeutic agents. The auxiliariesmust be “acceptable” in the sense of being compatible with the otheringredients of the composition and not deleterious to the recipientsthereof.

The invention further includes a compound of Formula I in combinationwith one or more other drug(s).

Compositions include e.g. those suitable for oral, sublingual,subcutaneous, intravenous, intramuscular, nasal, local, or rectaladministration, and the like, all in unit dosage forms foradministration.

For oral administration, the active ingredient may be presented asdiscrete units, such as tablets, capsules, powders, granulates,solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of theinvention may be presented in unit-dose or multi-dose containers, e.g.injection liquids in predetermined amounts, for example in sealed vialsand ampoules, and may also be stored in a freeze dried (lyophilized)condition requiring only the addition of sterile liquid carrier, e.g.water, prior to use.

Mixed with such pharmaceutically acceptable auxiliaries, e.g. asdescribed in the standard reference, Gennaro, A. R. et al., Remington:The Science and Practice of Pharmacy (20th Edition., Lippincott Williams& Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing),the active agent may be compressed into solid dosage units, such aspills, tablets, or be processed into capsules or suppositories. By meansof pharmaceutically acceptable liquids the active agent can be appliedas a fluid composition, e.g. as an injection preparation, in the form ofa solution, suspension, emulsion, or as a spray, e.g. a nasal spray.

For making solid dosage units, the use of conventional additives such asfillers, colorants, polymeric binders and the like is contemplated. Ingeneral any pharmaceutically acceptable additive which does notinterfere with the function of the active compounds can be used.Suitable carriers with which the active agent of the invention can beadministered as solid compositions include lactose, starch, cellulosederivatives and the like, or mixtures thereof, used in suitable amounts.For parenteral administration, aqueous suspensions, isotonic salinesolutions and sterile injectable solutions may be used, containingpharmaceutically acceptable dispersing agents and/or wetting agents,such as propylene glycol or butylene glycol.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material suitablefor said composition, said packaging material including instructions forthe use of the composition for the use as hereinbefore described. Theexact dose and regimen of administration of the active ingredient, or apharmaceutical composition thereof, may vary with the particularcompound, the route of administration, and the age and condition of theindividual subject to whom the medicament is to be administered. Ingeneral parenteral administration requires lower dosages than othermethods of administration which are more dependent upon absorption.However, a dosage for humans preferably contains 0.0001-100 mg per kgbody weight. The desired dose may be presented as one dose or asmultiple subdoses administered at appropriate intervals throughout theday. The dosage as well as the regimen of administration may differbetween a female and a male recipient.

In the compounds of generic Formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula I. For example, different isotopic forms of hydrogen (H)include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.

Isotopically-enriched compounds within generic Formula I can be preparedwithout undue experimentation by conventional techniques well known tothose skilled in the art or by processes analogous to those described inthe Schemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

The present disclosure describes the preparation of low molecular weightcompounds that show selective modulatory activity on the FSH receptor.The compounds of the invention can be used as (partial) antagonists ofthe FSH receptor.

The present invention therefore relates to FSHR antagonists as a meansfor the treatment and/or prevention of endometriosis, for the treatmentand/or prevention of pre-menopausal and peri-menopausalhormone-dependent breast cancer, for contraception, and for thetreatment of uterine fibroids and other menstrual-related disorders,such as dysfunctional uterine bleeding. Thus, the compounds according tothe invention can be used in therapy.

A further aspect of the invention resides in the use of compoundsaccording to the invention or a pharmaceutically acceptable salt thereoffor the treatment of FSH receptor-mediated diseases. Another aspect ofthe invention resides in the use of compounds or a pharmaceuticallyacceptable salt thereof having the general formula I for the treatmentof diseases wherein FSHR mediated signaling plays a role, in particularthose diseases wherein signaling can be inhibited by antagonizing theFSHR. These include, but are not limited to, the treatment andprevention of endometriosis, for the treatment and prevention ofpre-menopausal and pen-menopausal hormone-dependent breast cancer, forcontraception, and for the treatment of uterine fibroids and othermenstrual-related disorders, such as dysfunctional uterine bleeding.

In a further embodiment of the invention, a compound according to theinvention is used to treat endometriosis by providing improved controlover circulating levels of estrogens by dose titration thereby allowingoptimal control over the balance between efficacy and side effects.Moreover, the selective on-target interaction with the FSHR will notimpede LHR mediated signalling and associated production oftestosterone. With the improvement in tolerability, a compound accordingto the present invention can also provide a simple effective treatment,preferably by the oral route of administration, in an early stage of thedisease in a patient population familiar with contraceptive methods.Oral treatment is available by administration of a compound according tothe invention in a pharmaceutical formulation. During treatment with acompound according to the invention, regular bleeding can be partiallyor completely avoided (inducing amenorrhoea). This is particularlyuseful in the treatment of endometriosis since it diminishes or preventsretrograde menstruation and thereby minimizes recurrence of disease. Acompound according to the invention can also be used for contraception.A compound according to the invention has therapeutic and contraceptiveeffect while inducing a mostly atrophic or inactive endometrium. Thistreatment thereby avoids endometrial proliferation or hyperplasia.Compounds according to the invention are also useful for treatment ofother menstrual-related conditions such as fibroids and dysfunctionaluterine bleeding. Furthermore, in view of the property of the compounds,according to the invention, to diminish circulating levels of estrogens,a compound according to the invention is also very useful for treatmentof estrogen receptor positive breast cancer, either alone or incombination with an estrogen receptor antagonists such as tamoxifen or aselective estrogen receptor downregulator such as fulvestrant, inpre-menopausal and perimenopausal women.

Suitable methods to prepare the compounds of the present invention areoutlined below. The R-group numbering for compounds of general formulaI. (R1, R3 and R7-10) refers to the position of the substituentsrelative to the scaffold, based on the5,6-dihydropyrrolo[2,1-a]isoquinoline [X═C(R10), Y═C(R1)] numbering, asindicated below.

Compounds of general formula I are accessible by condensation ofcarboxylates of general structure II with tryptophanol derivatives ofgeneral formula III using methods well known to those skilled in theart. For example, reaction of II with III may be effected in an aproticsolvent such as THF or dichloromethane in the presence of a(commercially available) peptide coupling agent, like DCC, TBTU, HATU,EEDC, etc. and a suitable base, such as DiPEA. In turn, the requiredcarboxylates II may be obtained from the corresponding ethyl esters ofgeneral formula IV by standard saponification. Thus, treatment of ethylesters IV with NaOH in EtOH or dioxane/water mixtures at elevated orroom temperature provides carboxylates II.

2-Substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines of general formulaIV-a, in which R3=H, X═C(R10) and Y═C(R1), are accessible by reaction ofappropriately substituted dihydroquinolines of general structure V with(commercially available) ethyl bromopyruvate in the presence of a weakbase, such as NaHCO₃. Related conversions have been described in: A.Tatarov et al., Tetrahedron 66, 995-1006 (2010). The5,6-dihydropyrrolo[2,1-a]isoquinoline scaffold may be generated in analternative fashion using 1,3-dipolar cycloadditions of acetylenes withmunchnone intermediates as described extensively in the InternationalApplication WO 2009/098283 (N.V. Organon). In this process, oftenregioisomers are formed around positions 1 and 2 of the5,6-dihydropyrrolo[2,1-a]isoquinoline framework, which may be separatedby chromatography using methods such as HPLC or UPLC known to thoseskilled in the art.

Dihydroquinolines of general structure V may be obtained byBischler-Napieralski-type cyclocondensation of acylated phenethyl aminesVI, as described in: J. Jacobs et al., Tetrahedron Letters 50, 3698-3701(2009). Typically, the amides VI are dissolved in an aprotic solventsuch as toluene and treated with a dehydrating agent such as POCl₃, P₂O₅or polyphosphoric acid (PPA) at elevated temperature to accomplish thecyclocondensation to dihydroquinolines V.

Phenethyl amides VI may be obtained by standard acylation of phenethylamines VII-a with acyl chlorides of general formula VIII in an aproticsolvent, such as dichloromethane or THF, in the presence of a suitablebase such as DiPEA at elevated temperature or room temperature, aprocedure well known to those of skill in the art. Alkanoyl, alkenoyl oralkynoyl chlorides of general formula VIII, in which R1 has the samemeaning as previously defined, are commercially available.

The appropriate phenethyl amines of general structure VII are eithercommercially available or are prepared readily via chloromethylation ofappropriately substituted benzenes or pyridines, followed by conversioninto cyanomethyl derivatives and reduction of the nitrile functionality,yielding the required phenethyl amines VII. Phenethyl amines VII arealso accessible via Henry reaction of suitably substituted (commerciallyavailable) (hetero)aromatic aldehydes of general formula IX withnitromethane, followed by reduction of the intermediate nitro compoundsX by hydride reagents (LiAlH₄, boranes etc.) in solvents such as THF,according to procedures well documented in literature.

Introduction of the required substituents R3 in compounds of generalformula IV-b (R3=H) may be accomplished by organometal-catalyzedtransformations, e.g. using organopalladium catalysts, based onderivatives of general formula IV-b. An effective methodology tointroduce substituents R3 comprises Heck-type coupling withappropriately substituted halides R3-Br or R3-I. Heck-type couplingreactions are well known to those of skill in the art and typicallyinvolve the use of tetrakis(triphenylphosphine)palladium(0), palladiumchloride or palladium(II)acetate as catalysts in the presence of a basesuch as triethylamine, potassium carbonate or sodium acetate. Anoverview of Heck-type conversions may be found in I. P. Beletskaya etal., Chem. Rev. 100, 3009-3066 (2000). In specific cases, introductionof R3 may require the presence of a bromide functionality at C-3 of thescaffold. Thus, compounds of general formula IV-c may be generated byregioselective bromination of compounds IV-b using standard bromination(e.g. N-bromosuccinimide) conditions, well known to those skilled in theart. Subsequently, compounds of general formula IV may be prepared byorganopalladium-catalyzed transformations, such as Suzuki, Stille andSonogashira couplings. Compounds of general formula IV, in which R3contains a ketone functionality (e.g. R3=alkylcarbonyl) are accessibleby generation of an anion at C-3 of the pyrrole or imidazole ringstarting from compounds of general formula IV-b (deprotonation) or IV-c(transmetallation) with strong bases such as LDA in an aprotic solvent,followed by quenching with the appropriate acyl chloride (R3-Cl).

Compounds of general formula IV-d, in which Y═N, may be constructed bycyclization of bromides XI using Pd⁰ catalysis. In a typical experiment,the bromides XI are dissolved in an inert solvent, such as DMA andtreated with Pd(PPh₃)₄ in the presence of a suitable base, such asCs₂CO₃ at elevated temperature.

Imidazole derivatives XI are accessible by cyclization of appropriatelyfunctionalized (hetero)aryl ethyl amines XII with isocyanides XIII in aninert solvent, such as DMF, in the presence of a suitable base, such astriethyl amine. Related conversions have been described in: K. Nunami etal., J. Org. Chem. 59, 7635-7642 (1994) and K. Hiramatsu et al.,Synthesis, 781 (1990).

The appropriate (hetero)aryl ethyl amines of general structure XII areeither commercially available or may be prepared as described for thesynthesis of phenethyl amines VII (vide supra). In case X═N,2-bromination of the pyridine moiety may be effected using standardbromination conditions well known to those skilled in the art (e.g.N-bromosuccinimide), starting from suitably protected pyridines XIII, inwhich PG=protective group. For this purpose, the well knowntert-butoxycarbonyl (Boc) protective group can be used, which may beunleashed after bromide introduction using standard (acidic) conditions,to provide amines XII-a, in which X═N.

The required isocyanides XIII may be constructed in a multistep approachfrom commercially available aldehydes of general formula XVII. Thus,conversion of aldehydes XVII to unsaturated N-formyl esters XVI may beeffected with ethyl isocyanoacetate in the presence of a strong base,such as NaH, in an inert solvent such as THF. Subsequent bromination ofcompounds XVI using N-bromosuccinimide in CCl₄, conditions well known tothose of skill in the art, provides bromides XV. Compounds of generalformula XV may undergo dehydration of the N-formyl moiety using adehydrating agent such as POCl₃ in the presence of triethyl amine in aninert solvent such as dichloromethane, giving access to isocyanides ofgeneral formula XIII. The above delineated synthetic strategy has beendescribed in: K. Nunami et al., J. Org. Chem. 59, 7635-7642 (1994).

Preparation of heterocycles of general formula IV-e, in which X═N andY═C(R1), requires a related, but slightly adapted synthetic procedure.Reductive ring-closure of 2-bromopyridines of general formula XVIII maybe effected using (n-BuSn)₂ in the presence of a suitable palladium(II)catalyst, such as Pd(PPh₃)₂Cl₂ in an inert solvent such as DMF undermicrowave irradiation.

The required 2-bromopyridines of general formula XVIII may be preparedfrom 3-pyridyl ethyl bromides XX-a or their corresponding primaryalcohol derivatives XX-b, either by standard alkylation of bromides XIXat room temperature or elevated temperature in the presence of asuitable base (in case of XX-a) or by Mitsunobu-type alkylation (in caseof XX-b) using dialkyl azodicarboxylates such as DIAD in the presence oftriphenyl phosphine and a suitable base such as DiPEA. Both alkylationconditions may be considered part of the standard synthetic repertoireof those skilled in the art. Bromides of general formula XIX are eithercommercially available or accessible in elementary reaction steps fromcommercially available precursors. It is of importance to notice thatthe indicated conversions, such as XIX→XVIII→IV-e, may also be conductedwith the corresponding methyl esters instead of ethyl esters. Thoseskilled in the art will appreciate that the above described ensuingconversions to arrive at compounds of general formula I in which X═N andY═C(R1) are identical in case of methyl instead of ethyl esters andselection of the synthons will be guided by the (commercial)availability of the appropriately functionalized reagents.

The suitably functionalized 2-bromopyridines of general formula XX-a/bare accessible from commercially available 3-pyridyl aldehydes XXIII ina straightforward sequence of reaction steps, well known to those ofskill in the art. Methylenation of aldehydes XXIII using Wittig-typeconversions (e.g. reaction with CH₂═PPh₃ in an inert solvent such as THFin the presence of a suitable base, or alternatively, using Tebbe'sreagent) gives access to styrenes of general formula XXII. Ensuinghydroboration using appropriate borane derivatives, such as BH₃ or9-borabicyclononane (9-BBN), followed by oxidative work-up with e.g.hydrogen peroxide, provides 3-pyridyl ethanol derivatives XXI. Finally,2-pyridyl bromination using bromine in an inert solvent such asdichloromethane, then yields bromides of general formula XX-b. Inspecific cases, under the described conditions, concomitant brominationof the primary alcohol functionality occurs, giving access tobis-bromides XX-a.

For the synthesis of compounds of general formula I the overall approachindicated above was employed, making use of tailor-made functionalizedintermediates. This means that, depending on the required substituentsR1, R3, R7-R10 (where R-numbering refers to the atom numeration in thescaffold), either the required substituents are brought in place at thebeginning of the synthesis (i.e. R1=R1′, R3=R3′, etc.), or areintroduced at any stage judged to be convenient in the course of thesynthesis of the products of general formula I. In that case suitablealternative functionalities are introduced first, indicated as R1, R3′,R7′-R10′, which allow for the conversion into the desired R1, R3, R7-R10in one or more additional manipulations (i.e. conversion of XXIV to I asindicated above), with R1, R3, R7-R10 having the same meaning aspreviously defined. It is of importance to notice that such conversionsin most cases are not compatible with a free hydroxyl functionality,therefore a suitable hydroxyl-protecting group, as indicated in XXIV, isdeemed necessary. Appropriate hydroxyl-protecting groups comprisesilyl-ethers, such as tert-butyl-dimethylsilyl groups (TBDMS groups),which are introduced using standard conditions (i.e. treatment withTBDMS-Cl using an appropriate base, such as pyridine or DiPEA in anaprotic solvent such as dichloromethane or THF) well known to those ofskill in the art and may be deprotected by acidic or fluoride ion(tert-butyl ammonium fluoride, TBAF) treatment at any stage consideredto be convenient in the synthetic sequence leading to target derivativesof general formula I. Similarly, manipulation of substituents in anearlier stage of the synthetic protocol towards compound of generalformula I, might be performed on compounds of general formula IV-f, inwhich R1′, R3′, R7′-R10′ may be converted to R1, R3, R7-R10, asdescribed above to provide derivatives of general formula IV.

In order to manipulate substituents at the C1, C3, C7, C8, C9 or C10positions of the target scaffolds, halogen atoms like bromine, iodine ortriflates can be used. Triflates, in turn, may be present in the initialprecursors as methoxy groups, which, after demethylation using e.g.BBr₃, and subsequent triflation using e.g. triflic anhydride, providethe requisite tool compounds for further manipulation. Aromatic halidesor triflates can be converted via well known organometallic reactionslike Ullmann-, Suzuki-, Stille-, Sonogashira-, Heck- andBuchwald-protocols to substituents containing carbon-carbon single,double and triple bonds, carbon nitrogen bonds (anilines and amides) aswell as nitriles. These approaches are especially useful for connectingheterocyclic structures to specific positions of the scaffold, e.g. bycoupling of tailor-made heterocyclic structures (like boronates orstannanes).

Substituents on the aromatic ring (R7-R10) can often be introducedalready in the phenethyl amine precursors (e.g. VII or XII), carryingthem unchanged throughout the further synthetic process.

Tryptophanol derivatives of general structure III are eithercommercially available, or may be prepared in a sequence of reactionsteps from commercially available 3-cyanomethyl indole XXXII. Opticallypure tryptophanols III may be prepared from their correspondingdiastereomeric mixtures XXV using chiral separation technologies such asHPLC with chiral columns, well known to those of skill in the art. Thetryptophanols XXV are accessible from their corresponding amino acidprecursors XXVI using reducing agents such as borane complexes orLiAlH₄. In turn, amino acids XXVI can be obtained from theirN-butoxycarbonyl (Boc)-protected precursors XXVII by treatment withstrong acids such as trifluoroacetic acid or HCl. The required aminoacid framework in XXVII is obtained after basic hydrolysis of hydantoinsXXVIII. Typical conditions for this conversion are Ba(OH)₂ underelevated pressure and at increased temperature. The hydantoin moiety inXXVIII can be introduced by treating aldehydes or ketones XXIX withammonium carbonate in the presence of potassium cyanide.

Aldehydes XXIX-a, in which R13=H may be obtained by partial reduction ofcyanides XXX using DIBAL-H in toluene at low temperature (−50° C.).Ketones XXIX-b are accessible from aldehydes XXIX-a via a two-stepprocedure, well know to those skilled in the art. Thus, reaction ofXXIX-a with commercially available alkylmagnesium or alkyllithiumreagents in the presence of copper salts (or, alternatively, with alkylcuprates), followed by oxidation of the secondary alcohol moiety (usinga variety of oxidation protocols such as Swern-type oxidation orDess-Martin periodinane), gives access to XXIX-b.

Cyanides XXX, in turn, may be prepared by single or double alkylation ofXXXI. In a typical procedure, a strong base such as NaH or LDA is usedin an inert solvent such as diethyl ether with alkyl halides as alkyldonors. When alkyl dihalides such as 1,2-dichloroethane or1,4-dibromobutane are used, R14 and R15 together form a cycloalkyl ring.XXXI is accessible by Boc-protection of XXXII using methods welldocumented in literature. Typically, tert-butoxycarbonyl anhydride(Boc₂O) is used in an appropriate solvent such as dichloromethane in thepresence of a suitable base such as triethyl amine (in combination with4-dimethylamino pyridine DMAP) to functionalize XXXII with a Bocprotective group, as described in: Tetrahedron 65, 9015-9020 (2009).

The compounds of the invention inhibit FSH receptor activity. Allcompounds of the invention have a pIC50 of 5 or higher. Preferred arecompounds with a pIC50 of more than 7.

The invention is illustrated by the following examples.

GENERAL COMMENTS

The following abbreviations are used in the examples:DCM=dichloromethane, DMF=N,N-dimethylformamide, HCl=hydrogen chloride,NaHCO₃=sodium bicarbonate, MgSO₄=magnesium sulphate,THF=tetrahydrofuran, Na₂SO₄=sodium sulphate, DME=dimethoxyethane,LC-MS=liquid chromatography-mass spectrometry, HPLC=high-performanceliquid chromatography, MeCN=acetonitrile, Pd/C=palladium on carbon,HATU=2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate, DIPEA=N,N-Diisopropylethylamine,DMSO=dimethylsulfoxide, H₂=hydrogen, HBr=hydrogen bromide,NH₄Cl=ammonium chloride, N₂=nitrogen,TBTU=N,N,N′,N′-tetramethyl-O-(benzotriazol-1-YL)uroniumtetrafluoroborate, KCN=potassium cyanide, (NH₄)₂CO_(2,)=ammoniumbicarbonate, DCE=1,1-dichloroethane, Na₂CO₃=sodium carbonate,(BOC)₂O=Di-tert-butyl dicarbonate. The names of the final productsdescribed in the examples were generated using the convert name tostructure tool in ChemDraw version 9.01.

Example 1(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). N-(3,4-dimethoxyphenethyl)propionamide

To a solution of 3,4 methoxyphenethylamine (10 g) in DCM (100 ml) wereadded under a nitrogen atmosphere at 0° C. DIPEA (13.5 ml) andpropionylcloride (5.7 ml) dropwise over a period of 10 minutes. Thereaction mixture was stirred for 1 hour. The reaction mixture wasdiluted with DCM and sequentially washed with a aqueous 0.2M HClsolution, a aqueous saturated NaHCO₃ solution, water and brine. Theorganic layer was dried over MgSO₄, filtered and the solvents wereremoved under vacuum.

Yield: 13.03 g

MS (ESI) m/z: 238 (M+H)⁺.

(b). 1-ethyl-6,7-dimethoxy-3,4-dihydroisoquinoline

To a solution of compound 1a (12 g) in toluene (65 ml) was addeddropwise phosphorus oxychloride (12 ml) under nitrogen atmosphere at 95°C., over a period of 1 hour. The mixture was heated at 120° C. for 2hours and allowed to cool to room temperature overnight. The resultingHCl salt was collected by filtration and washed with diethylether togive the product as a brown solid

Yield: 15.48 g

(c). ethyl8,9-dimethoxy-1-methyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 1b (15.5 g) and potassium carbonate (16.5 g)in acetonitrile (100 ml) was added dropwise ethyl bromopyruvate (7.6ml). The reaction mixture was heated at 100° C. for 1 hour. The reactionmixture was filtered and concentrated. The residue was dissolved inethyl acetate, washed with water, dried over MgSO₄, filtered andconcentrated to a brown solid. The residue was purified bychromatography on silica gel eluting with hexane and increasing amountsof ethyl acetate. The pure fractions were collected and concentrated toa yellow solid.

Yield: 7.51 g

(d). ethyl8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Compound 1c (205 mg), phenylbromide (78 ul), triphenylphospine (34 mg)and cesium carbonate (459 mg) were suspended in degassed dioxane (4 ml).The mixture was further degassed for 10 minutes. Palladium (II)acetate(15 mg) was added and the reaction mixture was degassed for 5 minutesand heated at 100° C. for 18 hours. The reaction was not complete. Thereaction was degassed and recharged with triphenylphospine (34 mg, 0.13mmol) and palladium (II)acetate (15 mg). The reaction mixture was heatedfor another 18 hours. The reaction mixture was diluted with ethylacetate and water and filtered through celite. The organic phase wasdried (MgSO₄), filtered and concentrated to a brown oil. The residue waspurified by chromatography on silica gel eluting with hexane andincreasing amounts of ethyl acetate. The pure fractions were collectedand concentrated to a yellow solid.

Yield: 136 mg

MS (ESI) m/z: 392 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 7.43-7.38 (3H, m), 7.36-7.32 (2H, m), 7.26(1H, s, under CHCl₃ shift), 6.75 (1H, s), 4.06 (2H, 1, J=7.13 Hz), 3.95(3H, s), 3.90 (3H, s), 3.78 (2H, t, J=6.27 Hz), 2.85 (2H, t, J=628 Hz),2.67 (3H, s), 1.01 (3H, t, J=7.12 Hz)

(e).8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

To a suspension of compound 1d (135 mg) in ethanol (3.5 ml) was added aaqueous solution of 2M sodium hydroxide (1.7 ml). The reaction mixturewas heated at 65° C. for 2 nights. The reaction mixture was concentratedand extracted with ethyl acetate and a aqueous 1M HCl solution. Theorganic phase was dried (MgSO₄) and concentrated in vacuo.

Yield: 120 mg (mixture of starting material and product).

(f).(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (98 mg),1-hydroxybenzotriazole (69 mg), DIPEA (0.178 ml) and D-tryptophanol (78mg) were added to a solution of intermediate 1e (124 mg) in DMF (4 ml).The reaction mixture was stirred for 18 hours at ambient temperature.The reaction mixture was diluted with ethyl acetate and washedsequentially with a aqueous 1M HCl solution, a saturated aqueous NaHCO₃solution and brine. The reaction mixture was dried (MgSO₄), filtered andconcentrated to a pale brown oil. The residue was purified bychromatography on silica gel eluting with DCM and increasing amounts ofdiethylether and methanol. The pure fractions were collected andconcentrated in vacuo. The residue was purified by preparative HPLCeluting with acetonitrile and water.

Yield: 16.5 mg.

¹H NMR δ (ppm) (CHCl₃-d): 8.06 (1H, s), 7.55-7.74 (2H, m), 7.42-7.24(9H, m), 7.17 (1H, t, J=7.59 Hz), 7.08 (1H, t, J=7.5 Hz), 6.78 (1H, d,J=2.32 Hz), 6.74 (1H, s), 5.44 (1H, d, J=7.18 Hz), 4.32-4.23 (1H, m),3.94 (3H, s), 3.90 (3H, s), 3.844-3.73 (2H, m), 3.55 (1H, d, J=10.60Hz), 3.45 (1H, s), 2.86 (3H, t, J=6.56 Hz), 2.78-2.55 (5H, m).

Example 2N-(1-hydroxy-3-(1H-indol-3-yl)-2-methylpropan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl9-hydroxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of 1-methyl-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline(100 mg) in EtOH (5 ml) was added dropwise under a nitrogen atmosphereethylbromopyruvate (0.065 ml) and the reaction mixture was heated underreflux for 2 hours. The reaction mixture was allowed to cool to ambienttemperature, quenched with a saturated aqueous NaHCO₃ solution andextracted with ethyl acetate. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel eluting with heptane and increasing amountsof ethyl acetate.

Yield: 82 mg

(b). ethyl9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 2a (561 mg) in DMF (10 ml) were addedpotassium carbonate (810 mg) followed by 2-bromopropane (0.36 ml). Thereaction mixture was stirred at 65° C. overnight. The reaction mixturewas allowed to cool to ambient temperature, quenched with a saturatedaqueous NaHCO₃ solution and extracted with ethyl acetate. The organiclayer was dried (MgSO₄) and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluting with heptane andincreasing amounts of ethyl acetate.

Yield: 445 mg

MS (ESI) m/z: 330 (M+H)⁺.

(c). ethyl3-(3-fluorophenyl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Four identical solutions of intermediate 2b (1.0 g), 3-fluoroiodobenzene(423 μl,), triphenylphosphine (157 mg) and cesium carbonate (1.95 g) indioxane (20 ml) were degassed by bubbling through a gentle stream ofnitrogen for 30 minutes. Palladium acetate (67 mg) was added to eachreaction tube and the mixtures were degassed for a further 15 minutesbefore being sealed under nitrogen and heated to 110° C. for 6 hours.LC-MS indicated the reaction was approximately 50% complete, hence themixtures were degassed with nitrogen for 20 minutes and a furtheraliquot of the 3-fluoroiodobenzene (211 μl), palladium acetate (34 mg)and triphenylphospine (79 mg) were added to each. The mixtures weredegassed for a further 15 minutes before being sealed under nitrogen andheated for 16 hours at 110° C. LC-MS indicated the reactions were allapproximately 65% complete hence they were combined and filtered througha pad of celite and washed with dioxane and ethyl acetate. Ethyl acetatewas added to the solution and washed with water (3×). The organic layerwas passed through a hydrophobic frit and the solvent removed undervacuum. The residue was purified by chromatography on silica gel elutingwith petrol and increasing amounts of ethyl acetate. The targetfractions were combined and dried under vacuum to give a solid that wastriturated with diethyl ether to give the product, as an off-white solid

Yield: 3.34 g

MS (ESI) m/z: 424 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 7.44-7.37 (1H, m), 7.18 (1H, dd, J=7.7, 1.0Hz), 7.14-7.08 (3H, m), 6.90 (1H, s), 6.71 (1H, s), 4.62-4.54 (1H, m),4.16 (2H, q, J=7.1 Hz), 3.89-3.83 (5H, m), 2.93 (2H, t, J=6.5 Hz), 1.41(6H, d, J=6.1 Hz), 1.18 (3H, t, J=7.1 Hz).

(d).3-(3-fluorophenyl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

To a solution of compound 2c (0.5 g) in ethanol (12 ml) was added a 2Maqueous sodium hydroxide solution (6 ml). The reaction mixture washeated to 70° C. and stirred for 18 hours. The solvents were removedunder vacuum. The solid was suspended in ethyl acetate and acidifiedwith a aqueous 2M HCl solution to pH 1. The phases were separated andthe aqueous phase was re-extracted with ethyl acetate twice. Thecombined organic layers were washed with water and brine, before dryingover MgSO₄. The solvents were removed under vacuum to yield a pale brownsolid.

Yield: 0.45 g

(e). 2-amino-3-(1H-indol-3-yl)-2-methylpropan-1-ol

To a solution of alpha-methyl-DL-tryptophan (100 mg) in dry THF (10 ml)was added a borane-tetrahydrofuran complex (1.14 ml) dropwise. Thereaction mixture was heated at 65° C. for 4.5 hours. The reactionmixture was quenched with ethanol (3 ml). The reaction mixture wasconcentrated and extracted with ethyl acetate and water. The organiclayer was dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified by preparative HPLC eluting with acetonitrile and water.The pure fractions were collected and freezedried.

Yield: 33.7 mg

(f). tert-butyl 3-(cyanomethyl)-1H-indole-1-carboxylate

3-indoleacetonitrile (50 g), di-tert-butyl dicarbonate (76.8 g) and4-dimethylaminopyridine (1.96 g) were added to DCM (200 ml). The mixturewas stirred at room temperature overnight. The solution was washed withbrine and water and then dried (Na₂SO₄). The organic layer wasconcentrated and the residue was purified by chromatography on silicagel eluting with heptane and increasing amounts of ethyl acetate.

Yield: 68 g

(g). 1-(1H-indol-3-yl)cyclopropanecarbonitrile

Sodium hydride (4 equiv) was suspended in DMSO (˜6 ml/g). The mixturewas heated to 70-75° C. for 30 minutes. The mixture was allowed to coolto room temperature before adding it in portions to a cooled suspensionof compound 1f (1 equiv) and dibromo alkane (1 equiv) in diethylether(2.5× volume of DMSO) at 0° C. If the temperature rises above 5° C. aby-product is formed. The mixture was allowed to warm to roomtemperature and was stirred overnight to complete cyclisation. Thesuspension was diluted with water and acidified with a aqueous 2N HClsolution. The mixture was extracted with ethyl acetate twice and theorganic layers were dried (Na₂SO₄). The organic layer was concentratedbefore dissolving in dioxane. To the solution 4N HCl in dioxane wasadded (5 equiv) and was stirred overnight at room temperature. The crudemixture was diluted with water and basified with a aqueous 2N sodiumhydroxide solution. The aqueous layer was extracted with ethyl acetate(2×), dried (Na₂SO₄) and filtered. The organic layers were concentratedand the crude residue was used as such in the next step.

(h). 1-(1H-indol-3-yl)cyclopropanecarbaldehyde

Compound 2 g crude was dissolved in toluene. The solution was cooled to−45° C. and DIBAL-H (1.5-2.0 equiv) was added dropwise. The mixture wasallowed to warm to 0° C. and this was stirred for 1 hour at 0° C. Themixture was quenched with a mixture of diethylether and a saturatedaqueous NH₄Cl solution (1:1) and subsequently with a aqueous 1.6 N HClsolution (in 1:1 or 1:1.5 ratio to the Ether mixture). A thicksuspension was formed and the suspension was vigorously stirred at roomtemperature overnight. The mixture was diluted with water and basifiedwith a aqueous 2N sodium hydroxide solution. The aqueous layer wasextracted with ethyl acetate and the organic layer was dried (Na₂SO₄)and filtered. The organic layer was concentrated and used as such in thenext step.

(i). 5-(1-(1H-indol-3-yl)cyclopropyl)imidazolidine-2,4-dione

Compound 2h (1 equiv) was suspended in ethanol/water (1:1). To thesolution KCN (1.5 equiv) and (NH₄)₂CO₂ (3.0 equiv) were added and themixture was poured into a pressuretube. The mixture was heated to 80° C.in an oil bath for 6 hours. The mixture was allowed to cool to roomtemperature overnight. The mixture was diluted with water and acidifiedwith a aqueous 2N HCl solution. The aqueous layer was extracted withethyl acetate and diethylether. The organic layers were dried (Na₂SO₄),filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with heptane and increasing amounts of ethyl acetate.The product sticks on the column so rinsing with ethyl acetate ormethanol was needed.

Yield: 3 g

(j). 2-(1-(1H-indol-3-yl)cyclopropyl)-2-aminoacetic acid

Compound 2j (1 equiv) and barium hydroxide (4 equiv) were suspended inwater/dioxane (1:1) and poured into a microwave tube. The mixture washeated to 170° C. (external temperature of heating mantel) for minimumof 2 days. The mixture was filtrated and washed with water. The layerswere separated and the aqueous layer was concentrated. The solid waswashed with DCM and dried under vacuum (50° C.). crude 1.55 g

(k). 2-(1-(1H-indol-3-yl)cyclopropyl)-2-aminoethanol

Compound 2j (1 eq.) was dissolved in THF and cooled to 0° C. To thesolution a suspension of lithium aluminium hydride (6 equiv) in THF wasadded in portions. The mixture was allowed to warm to room temperatureand stirred for 30 minutes before heating it to reflux for 6 hours. Themixture was stirred overnight at room temperature. This was cooled to 0°C. and subsequently water and a aqueous 2N sodium hydroxide solutionwere added (1:2:1 ratio). The mixture was stirred for 30 min. allowingit to rise to room temperature. The mixture was filtered over celite andrinsed with diethylether. The mixture was dried (Na₂SO₄), filtered andconcentrated in vacuo.

Yield: 365 mg

(l).N-(1-hydroxy-3-(1H-indol-3-yl)-2-methylpropan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.2 mg),1-hydroxybenzotriazole (28.7 mg), triethylamine (0.084 ml) and 2e (762mg) were added to a solution of intermediate 2d (124 mg) in DMF (4 ml).The reaction mixture was stirred for 18 hours at ambient temperature.The reaction mixture was diluted with ethyl acetate and washedsequentially with a aqueous 1M HCl solution, a saturated aqueous NaHCO₃solution and brine. The reaction mixture was dried (MgSO₄), filtered andconcentrated to a pale brown oil. The residue was purified bypreparative HPLC eluting with acetonitrile and water.

Yield: 74 mg.

¹H NMR δ (ppm) (CHCl₃-d): 8.10 (1H, s), 7.77 (1H, d, J=8.19 Hz), 7.39(1H, d, J=8.13 Hz), 7.29-7.16 (6H, m), 7.13-6.92 (5H, m), 6.80 (1H, d,J=2.48 Hz), 6.72 (2H, d, J=12.30 Hz), 5.63 (1H, d, J=9.32 Hz), 4.61-4.54(1H, m), 4.40 (1H, td, J=8.65, 3.51 Hz), 3.87-3.72 (5H, m), 3.25 (1H, t,J=9.55 Hz), 2.92 (2H, t, J=6.54 Hz), 2.43-2.25 (2H, m), 1.64 (1H, t,J=12.86), 1.55 (7H, s), 1.46-1.35 (7H, m), 1.37-1.22 (3H, m)

Example 3N-(1-(1-(1H-indol-3-yl)cyclopropyl)-2-hydroxyethyl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 3 was prepared in an analogous fashion as described for example2, with compound 2k as reagent.

Yield: 27.6 mg.

¹H NMR δ (ppm) (CHCl₃-d): 8.00 (1H, s), 7.71 (1H, d, J=7.91 Hz), 7.37(1H, d, J=8.09 Hz), 7.29-7.16 (5H, m), 7.16-6.98 (5H, m), 6.77 (1H, d,J=2.44 Hz), 6.71 (2H, d, J=3.87 Hz), 5.91 (1H, d, J=8.00 Hz), 4.61-4.54(1H, m), 3.92-3.77 (5H, m), 3.72 (1H, td, J=7.87, 3.96), 3.54-3.47 (1H,m), 2.92 (2H, t, J=6.51 Hz), 2.67-2.61 (1H, m), 1.42 (6H, dd, J=8.67,6.07), 0.95-0.89 (2H, m), 0.85 (1H, dd, J=9.10, 2.61 Hz), 0.73 (1H, dd,J=8.99, 2.77 Hz)

Example 4(R)-3-(3,5-dimethylphenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). methyl3-(3,5-dimethylphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

A mixture of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylicacid (3.52) and 3,5-dimethylbenzoylchloride (3.25 g) in THF (3 ml) withmolecular sieves was heated in the microwave for 5 minutes at 150° C.The molecular sieves were filtered and acetic anhydride (4.55 g) andmethylpropiolate (1.38 g) were added. The mixture was stirred in themicrowave for 5 minutes at 150° C. The reaction mixture was diluted withethyl acetate and extracted sequentially with a aqueous 1M HCl solution,water and brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluting with heptane and increasing amounts of ethyl acetate.

Yield: 1.7 g mixture of regioisomers 2:8

MS (ESI) m/z: 392 (M+H)⁺.

(b).3-(3,5-dimethylphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A suspension of compound 4a (1.2 g) in a aqueous 3M lithium hydroxidesolution (3 ml) and dioxane (1 ml) was heated for 5 minutes in themicrowave at 180° C. The reaction mixture was acidified with a aqueous2N HCl solution to pH=2 and the precipitate was filtered.

Yield: 1.0 g mixture of regioisomers 2:8

MS (ESI) m/z: 378 (M+H)⁺.

(c).(R)-3-(3,5-dimethylphenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (360 mg),1-hydroxybenzotriazole (127 mg), DIPEA (0.46 ml) and D-tryptophanol (357mg,) were added to a solution of intermediate 4b (254 mg) in DMF (15ml). The reaction mixture was stirred for 18 hours at ambienttemperature. The reaction mixture was quenched with a saturated aqueousNaHCO₃ solution and extracted with ethyl acetate. The aqueous phase wasextracted with ethyl acetate and the combined organic layers were washedwith water (twice) and brine, dried (MgSO₄), filtered and concentratedin vacuo. The residue was purified by chromatography on silica geleluting with heptane and increasing amounts of ethyl acetate. The purefractions were collected and concentrated in vacuo. The residue waspurified by preparative HPLC eluting with acetonitrile and water. Thepure fractions were freezedried.

Yield: 99.2 mg

MS (ESI) m/z: 550 (M+H)⁺.

Example 5(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a mixture of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline (2 g) andpotassium carbonate (2.4 g) in ethanol (50 ml) was added dropwiseethylbromopyruvate (1.22 ml). The reaction mixture was refluxed for 3hrs. The reaction was allowed to cool to ambient temperature before asaturated aqueous NaHCO₃ solution was added. The aqueous phase wasextracted with ethyl acetate twice. The combined organic layers werewashed with brine. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluting with heptane and increasing amounts of ethyl acetate.

Yield: 2.1 g

MS (ESI) m/z: 302 (M+H)⁺.

(b). ethyl3-bromo-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

A solution of N-bromosuccinimide (0.91 g) in DCM (50 ml) was addeddropwise over a period of 45 minutes to a solution of intermediate 5a(1.88 g) in DCM (50 ml). The reaction mixture was stirred for 2 hoursbefore quenching with a saturated aqueous NaHCO₃ solution. The aqueousphase was extracted with DCM twice and the combined organics layers werewashed with water and brine, dried (MgSO₄) and filtered. The solventswere removed under vacuum to yield a crude solid that was purified bychromatography on silica gel eluting with petrol and increasing amountsof ethyl acetate to give the product, as an off white solid

Yield: 1.36 g

¹H NMR δ (ppm) (CHCl₃-d): 7.06 (1H, s), 6.86 (1H, s), 6.71 (1H, s),4.60-4.50 (1H, m), 4.33 (2H, q, J=7.12 Hz), 4.16-4.07 (2H, m), 3.87 (3H,s), 3.01 (2H, t, J=6.64 Hz), 1.41-1.36 (9H, m)

(c). ethyl8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (975 mg) was added to adegassed solution of intermediate 5b (60 mg), phenylboronic acid (625mg) and potassium carbonate (1.063 g) in a 10:1 mixture of DME:water (30ml). The mixture was degassed by gently bubbling through nitrogen for afurther 5 minutes before sealing under nitrogen and then heating to 90°C. for 3 hours. The reaction was allowed to cool to ambient temperaturebefore a saturated aqueous NaHCO₃ solution was added. The aqueous phasewas extracted with ethyl acetate twice. The combined organic layers werewashed with brine. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel eluting with heptane and increasing amounts of ethyl acetate.

Yield: 990 mg

MS (ESI) m/z: 378 (M+H)⁺.

(d).8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A aqueous 2M sodium hydroxide solution (2 ml) was added to a solution ofintermediate 5c (129 mg) in ethanol (5 ml). The mixture was heated to60° C. for 6 hours. The reaction was allowed to cool to ambienttemperature before a aqueous 2M HCl solution (3.1 ml) was added. Themixture was extracted with ethyl acetate and water. The organic layerwas washed with brine. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo.

Yield: 116 mg

MS (ESI) m/z: 350 (M+H)⁺.

(e).(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg),1-hydroxybenzotriazole (160 mg), DIPEA (0.39 ml) and D-tryptophanol (299mg) were added to a solution of intermediate 5d (275 mg) in DMF (15 ml).The reaction mixture was stirred for 18 hours at ambient temperature.The reaction mixture was quenched with a saturated aqueous NaHCO₃solution and extracted with ethyl acetate. The aqueous phase wasextracted with ethyl acetate and the combined organic layers were washedwith water twice and brine. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel eluting with heptane and increasing amountsof ethyl acetate.

Yield: 293.6 mg

MS (ESI) m/z: 522 (M+H)⁺.

Example 6(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). 8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A aqueous 2M sodium hydroxide (50 ml) was added to a solution ofintermediate 5a (3.01 g) in ethanol (100 ml). The mixture was heated to65° C. for 18 hours. The solvents were removed under vacuum and thecrude residue was suspended in ethyl acetate before acidifying to pH 2with a aqueous 2M HCl solution. A white precipitate was removed byfiltration and dried under vacuum (908 mg). The aqueous phase wasre-extracted with ethyl acetate. The combined organic layers were washedwith water (25 ml), dried (MgSO₄) and filtered. The solvents wereremoved under vacuum to give a grey solid. The two solids were combinedto give the product, as an off white solid that was used without furtherpurification.

Yield: 2.3 g

(b). (R)-1-(tert-butyldimethylsilyloxy)-3-(1H-indol-3-yl)propan-2-amine

To a solution of D-Tryptophanol (1.024 g) and imidazole (403 mg) in DCM(40 ml) and THF (8 ml) was added a solution of tert-butyldimethylsilylchloride (0.852 g) in DCM (5 ml) dropwise. The reaction was allowed towarm to room temperature overnight. The reaction mixture was quenchedwith a saturated aqueous NaHCO₃ solution and the reaction mixture wasextracted with dichloromethane. The aqueous phase was washed withdichloromethane and the combined organic layers were washed with brine,dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluting with heptane andincreasing amounts of ethyl acetate.

Yield: 1.11 g.

MS (ESI) m/z: 305 (M+H)⁺.

(c).(R)—N-(1-(tert-butyldimethylsilyloxy)-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 6b (2.34 g) was added to a solution of intermediate 6a (1.91 g)in DMF (75 ml). 1-Hydroxybenzotriazole (1.42 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.01 g) anddiisopropylethylamine (3.66 ml) were added to the reaction mixture andthe reaction mixture was stirred at ambient temperature for 72 hours.The reaction mixture was dissolved in ethyl acetate and washed withwater (3×). A precipitate was removed by filtration and determined to bepure product by HPLC (1.90 g). The aqueous phase was re-extracted withethyl acetate (3×) and the combined organic layers were washed withwater and a saturated aqueous NaHCO₃ solution, dried (MgSO₄) andfiltered. The solvents were removed under vacuum to give a pale brownsolid. The two collected solids were combined to give the product as apale brown solid which was used without further purification.

Yield: 3.56 g

Reaction conditions d and e were carried out in sequence withoutisolation of intermediate D.

(d/e).(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Palladium (II)acetate (4.5 mg) was added to a degassed solution ofintermediate 6c (112 mg), 4-fluorobenzene (53 mg), cesium carbonate (141mg) and triphenylphosphine (11 mg) in dioxane (3 ml) and the mixture wasdegassed with nitrogen for a further 15 minutes. The reaction tube wassealed and then heated to 100° C. for 18 hours. The reaction wasdetermined to be incomplete, hence a further aliquot of palladium(II)acetate (4.5 mg), triphenylphosphine (11 mg) and 4-fluorobenzene (53mg) was added. The mixture was degassed with nitrogen for 15 minutes,sealed under nitrogen and then heated to 100° C. for 18 hours. Thereaction was determined to be approximately 50% complete by HPLC hencethe solvents were removed under vacuum and the residue obtained waspartitioned between ethyl acetate (5 ml) and water. The aqueous phasewas re-extracted with ethyl acetate and the combined organic layers werewashed with water and then concentrated to dryness giving a dark brownoil. The oil was redissolved in THF (1 ml) before the addition oftetrabutylammonium fluoride in THF (0.3 ml, 1N), stirring for 2 hours.The solvents were removed under vacuum to give a dark oil that waspurified by preparative HPLC eluting with acetonitrile and water to givethe product, as an off white solid

Yield: 22 mg

MS (ESI) m/z: 540 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.10 (1H, s), 7.57 (1H, d, J=7.87 Hz), 7.37(1H, d, J=8.09 Hz), 7.03 (1H, s), 6.97-6.88 (3H, m), 6.76 (1H, s), 6.68(1H, s), 5.66 (1H, d, J=7.08 Hz), 4.37-4.30 (1H, m), 3.93 (2H, s), 3.88(2H, s), 3.75-3.62 (3H, m), 3.58 (1H, dd, J=10.91, 5.91 Hz), 3.07 (1H,s), 2.96-2.81 (4H, m).

Example 7(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 7 was prepared in an analogous fashion as described for example6. MS (ESI) m/z: 528 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.00 (1H, s), 7.57 (1H, d, J=7.9 Hz),7.39-7.35 (2H, m), 7.19 (1H, t, J=3.9 Hz), 7.12 (1H, t, J=7.5 Hz), 7.07(1H, s), 6.96-6.90 (4H, m), 6.68 (1H, s), 5.86 (1H, d, J=6.9 Hz),4.37-4.31 (1H, m), 3.93 (3H, s), 3.89 (3H, s), 3.81 (2H, t, J=6.6 Hz),3.68 (1H, d, J=11.4 Hz), 3.57 (1H, dd, J=11.0, 5.9 Hz), 3.05 (1H, s),2.92 (2H, t, J=6.7 Hz), 2.89-2.77 (2H, m).

Example 8(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 8 was prepared in an analogous fashion as described for example6.

MS (ESI) m/z: 552 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.09 (1H, s), 7.54 (1H, d, J=7.89 Hz), 7.33(1H, d, J=8.08 Hz), 6.93-6.82 (4H, m), 6.78 (1H, d, J=2.24 Hz), 6.68(1H, s), 5.73 (1H, d, J=6.81 Hz), 4.34-4.26 (1H, m), 3.90 (6H, d,J=16.25 Hz), 3.86-3.68 (4H, m), 3.72-3.61 (1H, m), 3.54 (1H, t, J=7.52Hz), 3.24 (1H, s), 2.93-2.69 (4H, m),

Example 9(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-nitrophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 9 was prepared in an analogous fashion as described for example6.

¹H NMR δ (ppm) (CHCl₃-d): 8.13 (1H, s), 8.11 (1H, s), 7.60 (1H, d,J=7.86 Hz), 7.43 (2H, d, J=8.56 Hz), 7.39 (1H, d, J=8.17), 7.26-7.19(1H, m), 7.15 (1H, d, J=7.56 Hz), 7.02-6.98 (2H, m), 6.70 (1H, s), 6.56(1H, s), 5.84 (1H, d, J=7.24 Hz), 4.45-4.35 (1H, m), 3.97-3.93 (3H, m),3.90-3.87 (3H, m), 3.84-3.79 (2H, m), 3.73-3.66 (2H, m), 3.02 (2H, dd,J=6.47, 3.36 Hz), 2.93 (2H, t, J=6.57 Hz), 2.78 (1H, s).

Example 10(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 10 was prepared in an analogous fashion as described forexample 6.

MS (ESI) m/z: 540 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.15 (1H, s), 7.57 (1H, d, J=7.89 Hz), 7.35(1H, d, J=8.09 Hz), 6.87 (1H, s), 6.75 (1H, s), 6.68 (1H, s), 5.72 (1H,d, J=6.98 Hz), 4.36-4.29 (1H, m), 3.90 (6H, d, J=17.08 Hz), 3.77 (2H, t,J=6.54 Hz), 3.69-3.54 (2H, m), 3.14 (1H, s), 2.96-2.80 (4H, m).

Example 11(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(methylamino)-3-(pyridin-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 11 was prepared in an analogous fashion as described forexample 6.

MS (ESI) m/z: 523 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.42-8.31 (2H, m), 8.12 (1H, s), 7.67-7.58(2H, m), 7.18-7.02 (4H, m), 6.92-6.85 (2H, m), 6.69 (1H, s), 4.39-4.33(1H, m), 4.02 (2H, t, J=6.49 Hz), 3.91 (6H, d, J=14.15 Hz), 3.77 (1H,dd, J=11.01, 3.36 Hz), 3.71-3.62 (1H, m), 3.01-2.88 (4H, m), 1.68 (3H,s).

Example 12(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(3-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 12 was prepared in an analogous fashion as described forexample 6.

MS (ESI) m/z: 552 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.09 (1H, s), 7.54 (1H, d, J=7.89 Hz), 7.33(1H, d, J=8.08 Hz), 6.93-6.82 (4H, m), 6.78 (1H, d, J=2.24 Hz), 6.68(1H, s), 5.73 (1H, d, J=6.81 Hz), 4.34-4.26 (1H, m), 3.90 (6H, d,J=16.25 Hz), 3.86-3.68 (4H, m), 3.72-3.61 (1H, m), 3.54 (1H, t, J=7.52Hz), 3.24 (1H, s), 2.93-2.69 (4H, m),

Example 13(R)-3-(4-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl3-bromo-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

A solution of N-bromosuccinimide (0.91 g) in DCM (50 ml) was addeddropwise over 45 minutes to a solution of intermediate 2b (1.88 g) inDCM (50 ml). The reaction mixture was stirred for 2 hours beforequenching with saturated aqueous sodium bicarbonate solution. Theaqueous phase was extracted with DCM twice and the combined organiclayers were washed with water and brine, dried (MgSO₄) and filtered. Thesolvents were removed under vacuum to yield a crude solid. The residuewas purified by chromatography on silica gel eluting with petrol andincreasing amounts of ethyl acetate.

Yield: 1.36 g

¹H NMR δ (ppm) (CHCl₃-d): 7.06 (1H, s), 6.86 (1H, s), 6.71 (1H, s),4.60-4.50 (1H, m), 4.33 (2H, q, J=7.12 Hz), 4.16-4.07 (2H, m), 3.87 (3H,s), 3.01 (2H, t, J=6.64 Hz), 1.41-1.36 (9H, m)

(b).3-bromo-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

Sodium hydroxide (1.33 g) in water (15 ml) was added to a solution ofintermediate 13a (1.33 g) in ethanol (15 ml). The mixture was heated to80° C. for 18 hours. The solvents were removed under vacuum and thecrude residue was suspended in ethyl acetate (30 ml) before acidifyingto pH 2 with a aqueous 2M HCl solution. The phases were separated andthe aqueous phase was re-extracted with ethyl acetate twice. Thecombined organic layers were washed with water and brine, dried (MgSO₄)and filtered. The solvents were removed under vacuum to give theproduct, as an off white solid.

Yield: 1.2 g

¹H NMR δ (ppm) (DMSO-d₆): 12.12 (1H, s), 7.24 (1H, s), 7.01 (1H, s),6.91 (1H, s), 4.67-4.60 (1H, m), 4.08-4.01 (2H, m), 3.77 (3H, s), 2.99(2H, t, J=6.60 Hz), 1.25 (6H, d, J=6.01 Hz)

(c).(R)-3-bromo-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g),1-hydroxybenzotriazole (0.47 g), triethylamine (1.32 ml) andD-tryptophanol (0.72 g) were added to a solution of intermediate 13b(1.2 g) in DMF (20 ml). The reaction mixture was stirred for 18 hoursand then the solvents were removed under vacuum to give an oily solid.The crude residue was partitioned between ethyl acetate and water andthe aqueous phase was re-extracted with ethyl acetate twice. Thecombined organic layers were washed with a aqueous 0.2M HCl solution,saturated aqueous sodium bicarbonate solution solution, water and brinebefore drying over magnesium sulfate. The solvents were removed undervacuum to give the product, as an off white solid

Yield: 1.73 g

¹H NMR δ (ppm) (DMSO-d): 10.76 (1H, s), 7.68 (1H, d, J=7.85 Hz), 7.34(2H, dd, J=16.04, 8.06 Hz), 7.15 (1H, s), 7.09-7.03 (2H, m), 7.02-6.96(2H, m), 6.93 (1H, s), 4.78 (1H, t, J=5.58 Hz), 4.56 (1H, t, J=6.08 Hz),4.20 (1H, d, J=7.52 Hz), 4.06-3.99 (3H, m), 3.77 (3H, s), 3.51 (1H, d,J=5.71 Hz), 3.46-3.42 (1H, m), 3.02-2.88 (4H, m), 1.30-1.24 (6H, m),

(d).(R)-3-(4-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Tetrakis(triphenylphosphine)palladium(0) (12.6 mg) was added to adegassed solution of intermediate 12c (60 mg), 4-fluorophenylboronicacid (23 mg) and potassium carbonate (45 mg) in a 10:1 mixture ofDME:water (4 ml). The mixture was degassed by gently bubbling throughnitrogen for a further 5 minutes before sealing under nitrogen and thenheating to 85° C. for 18 hours. The reaction was allowed to cool toambient temperature before water was added, extracting with ethylacetate (3×). The combined organic layers were passed through ahydrophobic frit and concentrated under vacuum. The crude brown residuewas purified by preparative HPLC eluting with acetonitrile and water togive the product, as an off white solid

Yield: 28 mg

¹H NMR δ (ppm) (CHCl₃-d): 8.10 (1H, s), 7.57 (1H, d, J=7.91 Hz), 7.37(1H, d, J=8.11 Hz), 6.97-6.88 (3H, m), 6.73 (1H, s), 6.68 (1H, s), 5.65(1H, d, J=7.08 Hz), 4.60-4.52 (1H, m), 4.36-4.29 (1H, m), 3.85 (3H, s),3.76-3.54 (4H, m), 3.09 (1H, t, J=5.28 Hz), 2.94-2.81 (4H, m), 1.40 (6H,d, J=6.12 Hz).

Example 14(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-m-tolyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 14 was prepared in an analogous fashion as described forexample 13.

MS (ESI) m/z: 564 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.00 (1H, s), 7.54 (1H, d, J=7.91 Hz), 7.34(1H, d, J=8.10 Hz), 6.86 (1H, s), 6.81 (1H, d, J=2.22 Hz), 6.68 (1H, s),5.66 (1H, d, J=6.86 Hz), 4.60-4.52 (1H, m), 4.32-4.24 (1H, m), 3.85 (3H,s), 3.77 (2H, t, J=6.62 Hz), 3.67-3.60 (1H, m), 3.51 (1H, dd, J=10.99,6.04 Hz), 3.14 (1H, s), 2.90 (2H, t, J=6.54 Hz), 2.84-2.67 (2H, m), 2.31(3H, s), 1.41 (6H, d, J=6.08 Hz).

Example 15(R)-3-(6-aminopyridin-3-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 15 was prepared in an analogous fashion as described forexample 13.

¹H NMR δ (ppm) (CHCl₃-d): 8.12 (1H, s), 7.58 (1H, d, J=7.91 Hz),7.39-7.03 (8H, m), 6.85 (1H, s), 6.70 (2H, d, J=10.30 Hz), 5.70 (1H, d,J=6.90 Hz), 4.59-4.50 (1H, m), 4.36-4.28 (1H, m), 3.86 (3H, s),3.81-3.74 (2H, m), 3.68 (1H, d, J=10.89), 3.60 (1H, dd, J=10.93, 5.87Hz), 3.15 (1H, s), 2.96-2.80 (4H, m), 1.43-1.39 (6H, m).

Example 16(R)-3-(3-chlorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 16 was prepared in an analogous fashion as described forexample 13

MS (ESI) m/z: 584,586 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.12 (1H, s), 7.58 (1H, d, J=7.91 Hz),7.39-7.03 (8H, m), 6.85 (1H, d, J=2.20 Hz), 6.70 (2H, d, J=10.30 Hz),5.70 (1H, d, J=6.90 Hz), 4.59-4.50 (1H, m), 4.36-4.28 (1H, m), 3.86 (3H,s), 3.81-3.74 (2H, m), 3.68 (1H, d, J=10.89 Hz), 3.60 (1H, dd, J=10.93,5.87 Hz), 3.15 (1H, s), 2.96-2.80 (4H, m), 1.43-1.39 (6H, m).

Example 17(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-(4-hydroxyphenyl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 17 was prepared in an analogous fashion as described forexample 13.

MS (ESI) m/z: 565 (M+H)⁺.

¹H NMR δ (ppm) (DMSO-d₆): 10.79 (1H, s), 7.97 (1H, d, J=8.19 Hz), 7.81(1H, s), 7.61 (1H, d, J=7.85 Hz), 7.41 (1H, s), 7.31 (1H, d, J=8.06 Hz),7.19-7.13 (2H, m), 7.04 (1H, t, J=7.55 Hz), 6.94 (2H, t, J=10.04 Hz),6.45 (2H, t, J=9.29 Hz), 4.73 (1H, s), 4.07-3.99 (1H, m), 3.84 (6H, d,J=17.14 Hz), 3.46 (1H, dd, J=10.80, 4.96 Hz), 2.98 (1H, dd, J=14.51,5.98 Hz), 2.86-2.75 (5H, m).

Example 183-(2-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 18 was prepared in an analogous fashion as described forexample 13.

MS (ESI) m/z: 568 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.06 (1H, s), 7.58 (1H, s), 7.39-7.28 (2H, m),6.93 (1H, d, J=15.19 Hz), 6.69 (2H, s), 5.74 (1H, t, J=8.35 Hz),4.61-4.52 (1H, m), 4.32 (1H, s), 3.89-3.64 (5H, m), 3.64-3.56 (1H, m),3.10 (1H, d, J=47.31 Hz), 2.95-2.82 (4H, m), 1.41 (8H, s).

Example 19(R)-3-(furan-2-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 19 was prepared in an analogous fashion as described forexample 13.

MS (ESI) m/z: 540 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.18 (1H, s), 7.63 (1H, d, J=7.85 Hz),7.40-7.32 (2H, m), 7.26-7.04 (3H, m), 6.98 (1H, s), 6.78 (1H, s), 6.69(1H, s), 6.45 (1H, d, J=3.29 Hz), 6.35 (1H, s), 6.28 (1H, d, J=6.93 Hz),4.59-4.49 (1H, m), 3.93 (2H, t, J=6.57 Hz), 3.86 (3H, s), 3.73 (1H, s),3.65 (1H, d, J=9.86 Hz), 3.19 (1H, s), 3.00-2.89 (4H, m), 1.40 (6H, d,J=6.08 Hz).

Example 20(R)-3-(3-cyanophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 20 was prepared in an analogous fashion as described forexample 13.

MS (ESI) m/z: 575 (M+H)⁺.

Example 21(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(3-(trifluoromethyl)phenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 21 was prepared in an analogous fashion as described forexample 13.

MS (ESI) m/z: 618 (M+H)⁺.

Example 22(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl3-formyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

N-butyl lithium (2.5 M in hexanes, 10.95 ml) was added dropwise to a 0°C. solution of diisopropylamine (3.3 g) in THF (60 ml), stirring for 10minutes before cooling to −78° C. A solution of intermediate 2b (7.5 g)in THF (90 ml) was carefully added keeping the reaction temperaturebelow −70° C., over 10 minutes. The solution was stirred at thistemperature for a further 20 minutes before the addition of DMF (2.0ml). The reaction mixture was stirred for a further 30 minutes. Thereaction mixture was allowed to warm to room temperature over 1 hour andwas then quenched by addition of a solution of saturated aqueous sodiumbicarbonate solution and water. The crude product was extracted intoethyl acetate (2×) and the combined organic layers were washed withwater and brine, dried (MgSO₄) and filtered. The solvents were removedunder vacuum to give a dark oil that was triturated with diethyl ether(60 ml) giving a solid that was removed by filtration and dried in air.The filtrate liquors were purified on silica gel (120 g) eluting with4:1 iso-hexane:ethyl acetate. Evaporation of the product fractions gaveadditional product as a crystalline off white solid. The two solids werecombined to give the product as an off white solid

Yield: 2.80 g

¹H NMR δ (ppm) (CHCl₃-d): 10.38 (1H, s), 7.13 (1H, s), 6.90 (1H, s),6.78-6.74 (1H, m), 4.74-4.67 (2H, m), 4.60-4.51 (1H, m), 4.38 (2H, dd,J=14.26, 7.13 Hz), 3.90-3.83 (3H, m), 3.05-2.97 (2H, m), 1.45-1.33 (9H,m).

(b). ethyl9-isopropoxy-8-methoxy-3-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Sodium hydride (60% dispersion in oil, 27 mg,) was added to a solutionof intermediate 22a (200 mg) and iso-propyltriphenylphosphonium iodide(290 mg) in THF (3 ml) before heating to 70° C. for 2 hours. Thereaction mixture was cooled to room temperature and then partitionedbetween ethyl acetate and water. The organic phase was concentrated todryness under vacuum to give a dark oil that was purified bychromatography on silica gel eluting with heptane and increasing amountsof ethyl acetate.

Yield: 160 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.10-7.05 (1H, m), 6.79-6.74 (1H, m), 6.70(1H, s), 6.18 (1H, s), 4.62-4.50 (1H, m), 4.33-4.21 (2H, m), 3.91-3.82(5H, m), 2.93 (2H, t, J=6.47 Hz), 1.96 (3H, s), 1.62 (3H, s), 1.39 (6H,d, J=6.09 Hz), 1.34 (3H, t, J=7.12 Hz).

(c). ethyl9-isopropoxy-8-methoxy-3-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

A aqueous 2N sodium hydroxide solution (1 ml) was added to a solution ofintermediate 22b (185 mg) in ethanol (2 ml) before heating to 70° C.four 18 hours. The reaction mixture was partitioned between ethylacetate and water. The aqueous phase was re-extracted with ethyl acetateand the combined organic layers were washed with water, dried oversodium sulphate, filtered and concentrated under vacuum to give theproduct as a yellow solid.

Yield: 155 mg

MS (ESI) m/z: 356 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 7.09 (1H, s), 6.86 (1H, s), 6.71 (1H, s), 6.18(1H, d, J=1.90 Hz), 4.58-4.51 (1H, m), 3.92-3.85 (5H, m), 2.98-2.92 (2H,m), 1.98 (3H, d, J=1.45 Hz), 1.65 (3H, d, J=1.24 Hz), 1.45-1.36 (6H, m),1.29-1.20 (1H, m).

(d).3-isobutyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A solution of intermediate 22c (75 mg) in 1:2 DCM:methanol (5 ml) waspassed through the H-Cube hydrogenator at 1 ml/min/30° C./60 bar H₂ overa 10% Pd/C cartridge until the reaction was determined to be complete byHPLC. The solvents were removed under vacuum to give the product as acolourless oil

Yield: 51 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.08 (1H, s), 6.83 (1H, s), 6.71 (1H, s),4.59-4.51 (1H, m), 4.02-3.95 (2H, m), 3.90-3.83 (3H, m), 3.49 (1H, s),3.01-2.88 (4H, m), 2.02-1.94 (1H, m), 1.39 (6H, d, J=6.07 Hz), 0.97 (6H,d, J=6.62 Hz).

(e).(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (41 mg) wasadded to a solution of intermediate 22d (50 mg) and1-hydroxybenzotriazole (20 mg) in DMF (1 ml). The mixture was stirredfor 5 minutes before the addition of D-tryptophanol (28 g), stirring fora further 18 hours. The reaction mixture was partitioned between ethylacetate and water. The organic phase was separated and washed withwater, dried by passing through a hydrophobic frit and then concentratedto dryness to give an orange oil. The crude oil was purified by reversephase preparative HPLC to give the product as a white solid

Yield: 28 mg

MS (ESI) m/z: 530 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.12 (1H, s), 7.73 (1H, d, J=7.73 Hz), 7.40(1H, d, J=7.95 Hz), 7.25-7.16 (2H, m), 7.12 (1H, d, J=2.33 Hz), 6.88(1H, s), 6.71-6.67 (1H, m), 6.08-6.02 (2H, m), 4.60-4.52 (1H, m),4.45-4.39 (1H, m), 3.96-3.88 (2H, m), 3.85 (3H, s), 3.82 (1H, dd,J=6.72, 3.72 Hz), 3.79-3.71 (1H, m), 3.58-3.53 (1H, m), 3.20-3.06 (2H,m), 2.97-2.80 (4H, m), 1.97-1.87 (1H, m), 1.43-1.34 (6H, m), 0.94-0.87(6H, m).

Example 23(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 23 was prepared in an analogous fashion as described forexample 13, starting with 22c en performing step e.

MS (ESI) m/z: 528 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.07 (1H, s), 7.69 (1H, d, J=7.85 Hz), 7.37(1H, d, J=8.06 Hz), 7.23-7.18 (1H, m), 7.16-7.11 (1H, m), 7.07 (1H, d,J=2.40 Hz), 6.75 (1H, s), 6.68 (1H, s), 6.45 (1H, d, J=6.73 Hz), 5.88(1H, s), 4.57-4.50 (1H, m), 4.48-4.42 (1H, m), 3.85 (3H, s), 3.82-3.71(4H, m), 3.40 (1H, s), 3.06 (2H, d, J=6.97 Hz), 2.94-2.87 (2H, m), 1.72(2H, s), δ 1.56 (6H, s), 1.43-1.37 (6H, m).

Example 24(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Lithium diisopropylamide (0.2 M stock solution, 2.28 ml) was addeddropwise to a −78° C. solution of intermediate 2b (100 mg) in dry THF (2ml) under a nitrogen atmosphere. The mixture was stirred for 30 minutesat −78° C. before the addition of isobutyryl chloride (64 μl) in oneportion, stirring for a further 15 minutes at −78° C. then allowing towarm to room temperature over 10 minutes. The reaction mixture wasquenched with saturated aqueous sodium bicarbonate solution and thenpartitioned between water and ethyl acetate (3×). The combined organiclayers were passed through a hydrophobic frit and concentrated undervacuum. The residue was purified by chromatography on silica gel elutingwith petrol and increasing amounts of ethyl acetate to give the product,as a clear gum

Yield: 100 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.09 (1H, s), 6.77 (1H, s), 6.72 (1H, s),4.60-4.49 (1H, m), 4.33 (2H, q, J=7.1 Hz), 4.17 (2H, t, J=6.7 Hz), 3.87(3H, s), 3.61-3.48 (1H, m), 2.97 (2H, t, J=6.6 Hz), 1.42-1.31 (9H, m),1.17 (6H, d, J=6.8 Hz).

(b).3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

Sodium hydroxide (29 mg) in water (0.3 ml) was added to a solution ofintermediate 24a (97 mg) in ethanol (3 ml). The mixture was heated for 6hours at 70° C. The solvents were removed under vacuum and the cruderesidue was dissolved in water and washed with diethyl ether (3×). Theaqueous phase was acidified to ˜pH 3 with a aqueous 2N HCl solution andthen extracted with DCM (3×). The combined organic layers were passedthrough a hydrophobic frit and concentrated under vacuum to give theproduct, as grey solid

Yield: 75 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.11 (1H, s), 6.90 (1H, s), 6.73 (1H, s),4.60-4.51 (1H, m), 4.17 (2H, t, J=6.6 Hz), 3.88 (3H, s), 3.63-3.52 (1H,m), 3.00 (2H, t, J=6.5 Hz), 1.40 (6H, d, J=6.1 Hz), 1.19 (6H, d, J=6.8Hz).

(c.)(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg) wasadded to a solution of intermediate 24b (74 mg), diisopropylethylamine(105 μl), 1-hydroxybenzotriazole (41 mg) and D-tryptophanol (46 mg) indry DMF (2 ml). The mixture was stirred at room temperature for 60hours. Water was added and the product was extracted into ethyl acetate(5×). The combined organic layers were passed through a hydrophobic fritand concentrated under vacuum to give a pale brown oil. The residue wasredissolved in DMSO and purified by preparative HPLC eluting withacetonitrile and water to give the product, as an off white solid

Yield: 47 mg

MS (ESI) m/z: 544 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.22 (1H, s), 7.72 (1H, d, J=7.8 Hz), 7.38(1H, d, J=8.0 Hz), 7.27-7.12 (2H, m), 7.11 (1H, d, J=2.4 Hz), 6.95 (1H,s), 6.70 (1H, s), 6.43 (1H, d, J=7.3 Hz), 6.22 (1H, s), 4.58-4.43 (2H,m), 4.38-4.24 (2H, m), 3.86 (3H, s), 3.84-3.71 (2H, m), 3.46-3.36 (1H,m), 3.14 (2H, d, J=6.9 Hz), 2.96-2.89 (3H, m), 1.39 (6H, d, J=6.1 Hz),1.10 (6H, t, J=6.5 Hz).

Example 25(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-pivaloyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 25 was prepared in an analogous fashion as described forexample 24.

MS (ESI) m/z: 558 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.11 (1H, s), 7.72 (1H, d, J=7.8 Hz), 7.41(1H, d, J=8.0 Hz), 7.28-7.15 (2H, m), 7.11 (1H, s), 6.91 (1H, s), 6.68(1H, s), 6.12 (1H, d, J=6.7 Hz), 6.07 (1H, s), 4.59-4.51 (1H, m),4.40-4.30 (1H, m), 3.90-3.71 (7H, m), 3.32 (1H, t, J=5.4 Hz), 3.17-3.05(2H, m), 2.98-2.87 (2H, m), 1.41 (6H, t, J=5.6 Hz), 1.25 (9H, s).

Example 26(R)-3-butyryl-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 26 was prepared in an analogous fashion as described forexample 24.

MS (ESI) m/z: 544 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.16 (1H, s), 7.72 (1H, d, J=7.85 Hz), 7.39(1H, d, J=8.07 Hz), 6.95 (1H, s), 6.71 (1H, s), 6.48 (1H, d, J=7.35 Hz),6.24 (1H, s), 4.58-4.36 (4H, m), 3.92-3.69 (4H, m), 3.22-3.08 (2H, m),2.93 (2H, t, J=6.79 Hz), 2.89-2.70 (3H, m), 1.39 (6H, d, J=6.08 Hz),0.89 (3H, t, J=7.39 Hz).

Example 27(R)-3-(cyclopropanecarbonyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 27 was prepared in an analogous fashion as described forexample 24.

MS (ESI) m/z: 542 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.31 (1H, s), 7.70 (1H, d, J=7.8 Hz),7.36-7.29 (2H, m), 7.17 (1H, t, J=3.9 Hz), 7.15-7.07 (2H, m), 7.02 (1H,s), 6.70 (1H, s), 6.57 (1H, s), 4.57-4.41 (2H, m), 4.38 (2H, t, J=6.7Hz), 3.86 (3H, s), 3.90-3.64 (2H, m), 3.26 (1H, t, J=5.4 Hz), 3.11 (2H,d, J=7.0 Hz), 2.94 (2H, t, J=6.7 Hz), 2.43-2.34 (1H, m), 1.38 (6H, d,J=6.1 Hz), 1.21-1.16 (2H, m), 0.96-0.90 (2H, m).

Example 28(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(thiophene-2-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 28 was prepared in an analogous fashion as described forexample 24.

MS (ESI) m/z: 584 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.02 (1H, s), 7.68-7.62 (2H, m), 7.59 (1H, dd,J=3.8, 1.1 Hz), 7.34 (1H, d, J=8.1 Hz), 7.19 (1H, t, J=7.7 Hz),7.14-7.07 (3H, m), 7.04 (1H, d, J=2.3 Hz), 6.73 (2H, d, J=11.8 Hz), 6.66(1H, d, J=6.9 Hz), 4.58-4.51 (1H, m), 4.22-4.14 (3H, m), 3.87 (3H, s),3.51-3.47 (2H, m), 3.01-2.94 (2H, m), 2.91-2.81 (3H, m), 1.40 (6H, d,J=6.1 Hz).

Example 29(R)-3-benzoyl-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 29 was prepared in an analogous fashion as described forexample 24.

MS (ESI) m/z: 578 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 7.97 (1H, s), 7.75 (2H, d, J=7.7 Hz), 7.63(1H, d, J=7.9 Hz), 7.57 (1H, t, J=7.4 Hz), 7.43 (2H, t, J=7.6 Hz), 7.33(1H, d, J=8.1 Hz), 7.19 (2H, t, J=8.2 Hz), 7.11 (2H, t, J=7.6 Hz), 7.03(1H, d, J=2.3 Hz), 6.84 (1H, s), 6.70 (1H, s), 4.58-4.51 (1H, m),4.19-4.13 (1H, m), 4.03 (2H, t, J=6.7 Hz), 3.87 (3H, s), 3.52-3.43 (2H,m), 2.96-2.82 (5H, m), 1.41 (6H, d, J=6.1 Hz).

Example 30(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). 6,7-diisopropoxy-1-methyl-3,4-dihydroisoquinoline

A solution of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline (35.8 g) inaqueous HBr (48%, 175 ml) was heated at 90° C. for 4.5 hours. 11%starting material, 71% mono-demethyl and 18% di-demethyl productaccording to LC-MS. Toluene was added to the reaction mixture and thesolvent was evaporated in vacuo. The residue was dissolved in DMF (300ml), before addition of potassium carbonate (82 g). 2-Bromopropane (41.7ml) was added to the stirred suspension before heating at 70° C. for 18hrs. 40% conversion according to LC-MS, hence a further aliquot of2-bromopropane and potassium carbonate were added to the reactionmixture and heated at 70° C. for 3 hrs. The reaction mixture wasextracted with ethyl acetate and water. The aqueous layer was washedwith ethyl acetate and the combined organic layers were washedsequentially with water and brine, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel with petrol and increasing amounts of ethyl acetate, yieldingin a pale brown solid 0.7 g, consisting of 82% mono-demethyl product, 8%di-demethyl product and 12% starting material. This material was usedwithout further purification.

(b). ethyl8,9-diisopropoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a mixture of 30a (26.8 g) and potassium carbonate (35 g) inacetonitrile (270 ml) was added dropwise ethylbromopyruvate (17.3 ml).The reaction mixture was refluxed for 3 hrs. The reaction was allowed tocool to ambient temperature before a saturated aqueous NaHCO₃ solutionwas added. The aqueous phase was extracted with ethyl acetate twice. Thecombined organic layers were washed with brine. The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluting with petrol andincreasing amounts of ethyl acetate. The pure fractions of the desiredproduct were concentrated in vacuo.

(c.) ethyl8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Compound 30b (232 mg), phenylbromide (117 mg), triphenylphosphine (34mg) and cesium carbonate (459 mg) were suspended in degassed dioxane (4ml). Palladium(II)acetate (15 mg) was added and the mixture was furtherdegassed for 5 minutes and heated at 100° C. for 18 hours. The reactionmixture was degassed and recharged with triphenylphosphine andpalladium(II)acetate and heated for a further 18 hours. The reactionmixture was diluted with ethyl acetate and water and filtered throughcelite. The organic phase was dried (MgSO₄), filtered and concentratedto a yellow oil. The residue was purified by chromatography on silicagel with hexane and increasing amounts of ethyl acetate. The purefractions were concentrated to a colorless oil.

Yield: 162 mg

MS (ESI) m/z: 434 (M+H)⁺.

(d.)8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A aqueous 2N sodium hydroxide solution (21.9 ml) was added to a solutionof intermediate 30c (161 mg) in ethanol (4 ml). The mixture was heatedfor 18 hours at 60° C. The solvents were removed under vacuum and thecrude residue was partitioned between a aqueous 1N HCl solution andethyl acetate. The organic phase was dried (MgSO₄), filtered andconcentrated to a pale brown solid.

Yield: 145 mg

MS (ESI) m/z: 406 (M+H)⁺.

(e.)(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104 mg) wasadded to a solution of intermediate 30d (145 mg), diisopropylethylamine(188 μl), 1-hydroxybenzotriazole (73 mg) and D-tryptophanol (82 mg) indry DMF (4 ml). The mixture was stirred at room temperature for 18hours. The reaction mixture was diluted with ethyl acetate and washedsequentially with a aqueous 1N HCl solution, a saturated aqueous NaHCO₃solution and brine. The organic layer was dried (MgSO₄) and concentratedin vacuo to a pale brown oil. The residue was purified by chromatographyon silica gel with DCM and increasing amounts of methanol (max. 7% inDCM). The pure fraction were collected and concentrated in vacuo,yielding in a pale yellow solid.

¹H NMR δ (ppm) (CHCl₃-d): 8.32 (1H, s), 7.52 (1H, d, J=7.89 Hz),7.35-7.19 (6H, m), 7.20-7.06 (3H, m), 6.83 (1H, s), 6.78 (1H, d, J=2.3Hz), 6.71 (1H, s), 5.64 (1H, d, J=6.95), 4.54-4.40 (2H, m), 4.33-4.23(1H, m), 3.73 (2H, t, J=6.50 Hz), 3.61 (1H, d, J=10.88 Hz), 3.51 (1H,dd, J=10.94, 5.95 Hz), 3.31 (1H, s), 2.88-2.68 (4H, m), 1.34 (12H, dd,J=11.62, 6.09 Hz).

Example 31(R)-3-(3-fluorophenyl)-9-hydroxy-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Compound 31a was prepared in an analogous fashion as described forexample 5c.

(b). ethyl3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 31a (124 mg) in DCE (2 ml) was added aluminiumchloride (120 mg). The mixture was heated at 50° C. for 75 minutes. Thereaction mixture was diluted with DCM and quenched with solid NaHCO₃ andacidified with a aqueous 2M HCl solution. The organic layer was washedwith water and brine, dried (Na₂SO₄), filtered and concentrated in vacuoto give a pale yellow oil.

Yield: 114 mg (the product is a mixture of regioisomers (20:80). Thecrude product used without further purification.

(c)3-(3-fluorophenyl)-9-hydroxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

To a solution of the mixture of isomers 31b (114 mg) in ethanol (2 ml)was added a aqueous 2M sodium hydroxide solution (0.75 ml). The mixturewas heated at 50° C. for 18 hrs. The reaction mixture was diluted withethyl acetate and extracted with a aqueous 2M HCl solution. The organiclayer was washed with water, brine, dried (MgSO₄), filtered andconcentrated in vacuo to yield a pale yellow oil.

Yield: 110 mg

(d.)(R)-3-(3-fluorophenyl)-9-hydroxy-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (87 mg) wasadded to a solution of a mixture of regioisomers 31c (110 mg),triethylamine (126 μl), 1-hydroxybenzotriazole (43 mg) andD-tryptophanol (71 mg) in dry DMF (2 ml). The reaction mixture wasstirred at room temperature for 60 hours. The solvent was removed undervacuum to give a yellow oil. The oil was redissolved in ethyl acetateand washed with water (3×). The combined organic layers were passedthrough a hydrophobic frit and concentrated under vacuum. The cruderesidue was redissolved in MeCN and purified by preparative HPLC,eluting with acetonitrile and water to give the product as an off-whitesolid

Yield: 16 mg

¹H NMR δ (ppm) (CHCl₃-d): 8.4 (1H, s), 7.65-7.55 (2H, m), 7.19-7.25 (3H,m), 7.19-7.00 (7H, m), 6.68 (1H, s), 6.00 (1H, d, J=7.25), 5.82 (1h,bs), 4.40-4.30 (1H, m), 3.90 (3H, s), 3.67-3.53 (2H, m), 2.98-2.70 (6H,m).

Example 32(R)-9-(allyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl3-(3-fluorophenyl)-9-hydroxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Boron tribromide (1.05 ml) was added dropwise to a −40° C. solution ofintermediate 2c (890 mg) in DCM (25 ml) under a nitrogen atmosphere. Thereaction mixture was stirred for 30 minutes, then a further aliquot ofboron tribromide (1.05 ml) was added dropwise and the mixture stirredfor a further 2 hours at −40° C. The reaction was quenched with waterand the aqueous phase was extracted with DCM (3×). The combined organiclayers were passed through a hydrophobic frit and the solvent wasremoved under vacuum. The residue was purified by chromatography onsilica gel eluting with heptane and increasing amounts of ethyl acetateto give the product as a pale pink solid.

Yield: 550 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.45-7.37 (1H, m), 7.22-7.08 (4H, m), 6.90(1H, s), 6.69 (1H, s), 5.58 (1H, s), 4.16 (2H, q, J=7.1 Hz), 3.90 (3H,s), 3.86 (2H, t, J=6.5 Hz), 2.92 (2H, t, J=6.5 Hz), 1.18 (3H, t, J=7.1Hz).

(b). ethyl9-(allyloxy)-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Allyl chloride (24 μl) was added to a solution of intermediate 32a (76mg) and potassium carbonate (42 mg) in DMF (2 ml), heating to 60° C. for18 hours. The mixture was concentrated to dryness under vacuum and theresidue was suspended in water. The crude product was extracted intoethyl acetate (3×) and the combined organic layers were passed through ahydrophobic frit and concentrated under vacuum to give the product as anoff white solid

Yield: 82 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.45-7.37 (1H, m), 7.20-7.09 (4H, m), 6.89(1H, s), 6.71 (1H, s), 6.18-6.07 (1H, m), 5.46 (1H, dq, J=17.3, 1.6 Hz),5.34 (1H, d, J=1.5 Hz), 4.67 (2H, d, J=5.4 Hz), 4.16 (2H, q, J=7.12 Hz),3.90-3.82 (5H, m), 2.97-2.89 (2H, m), 1.18 (3H, t, J=7.1 Hz).

(c.)9-(allyloxy)-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

Sodium hydroxide (23 mg) in water (0.3 ml) was added to a solution ofintermediate 32b (80 mg) in ethanol (3 ml). The mixture was heated to80° C. for 3 hours. The solvents were removed under vacuum and theresidue redissolved in water and washed with diethyl ether (3×). Theaqueous layer was acidified to ˜pH 4 with a aqueous 4M HCl solution andextracted into DCM (3×) and ethyl acetate (3×). The combined organiclayers were passed through a hydrophobic frit and concentrated undervacuum to give the product, as an off white solid

Yield: 73 mg

MS (ESI) m/z: 394 (M+H)⁺.

(d.)(R)-9-(allyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg) wasadded to a solution of intermediate 32c (71 mg), diisopropylethylamine(94 μl), 1-hydroxybenzotriazole (37 mg) and D-tryptophanol (41 mg) indry DMF (2 ml). The reaction mixture was stirred at room temperature for60 hours. The solvent was removed under vacuum to give a yellow oil. Theoil was redissolved in ethyl acetate and washed with water (3×). Thecombined organic layers were passed through a hydrophobic frit andconcentrated under vacuum. The crude residue was redissolved in MeCN andpurified by preparative HPLC eluting with acetonitrile and water to givethe product as an off-white solid

Yield: 14 mg, 9%.

MS (ESI) m/z: 566 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.08 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.36(1H, d, J=8.1 Hz), 7.26-7.15 (2H, m), 7.11 (1H, t, J=7.5 Hz), 7.05-6.96(4H, m), 6.88 (1H, d, J=2.3 Hz), 6.70 (2H, d, J=11.1 Hz), 6.17-6.06 (1H,m), 5.69 (1H, d, J=7.0 Hz), 5.45 (1H, dd, J=17.3, 1.7 Hz), 5.32 (1H, dd,J=10.5, 1.5 Hz), 4.65 (2H, d, J=5.4 Hz), 4.37-4.29 (1H, m), 3.88 (3H,s), 3.77 (2H, t, J=6.6 Hz), 3.70-3.55 (2H, m), 3.06 (1H, s), 2.94-2.80(4H, m).

Example 33(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxyethoxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 33 was prepared in an analogous fashion as described forexample 32.

MS (ESI) m/z: 584 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.35 (1H, s), 7.56 (1H, d, J=7.9 Hz), 7.34(1H, d, J=8.1 Hz), 7.26-7.14 (2H, m), 7.13-6.95 (5H, m), 6.87 (1H, d,J=2.3 Hz), 6.68 (2H, d, J=6.6 Hz), 5.76 (1H, d, J=7.0 Hz), 4.37-4.27(1H, m), 4.20 (2H, t, J=4.8 Hz), 3.85 (3H, s), 3.81 (2H, t, J=4.8 Hz),3.75 (2H, t, J=6.5 Hz), 3.68-3.53 (2H, m), 3.47 (3H, s), 2.95-2.78 (4H,m).

Example 34(R)-9-(benzyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 34 was prepared in an analogous fashion as described forexample 32.

MS (ESI) m/z: 616 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.41 (1H, s), 7.53 (1H, d, J=7.9 Hz), 7.45(2H, d, J=7.5 Hz), 7.35 (2H, t, J=7.5 Hz), 7.30-7.23 (2H, m), 7.22-7.09(2H, m), 7.10-7.02 (2H, m), 6.98-6.91 (3H, m), 6.79 (1H, d, J=2.4 Hz),6.67 (2H, d, J=4.2 Hz), 5.76 (1H, d, J=7.1 Hz), 5.13 (2H, s), 4.36-4.26(1H, m), 3.85 (3H, s), 3.69 (2H, t, J=6.4 Hz), 3.62-3.48 (2H, m), 3.39(1H, s), 2.91-2.72 (4H, m).

Example 35(R)-9-(cyclopentylmethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 35 was prepared in an analogous fashion as described forexample 32.

MS (ESI) m/z: 594 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.01 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.36(1H, d, J=8.10 Hz), 7.24-7.17 (2H, m), 7.12 (1H, t, J=7.5 Hz), 7.08-6.96(4H, m), 6.88 (1H, d, J=2.3 Hz), 6.75 (1H, s), 6.68 (1H, s), 5.68 (1H,d, J=6.9 Hz), 4.83-4.78 (1H, m), 4.36-4.30 (1H, m), 3.85 (3H, s), 3.77(2H, t, J=6.6 Hz), 3.71-3.55 (2H, m), 3.06 (1H, s), 2.94-2.80 (4H, m),2.04-1.90 (6H, m), 1.91-1.82 (2H, m).

Example 36(R)-9-(cyclopropylmethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 36 was prepared in an analogous fashion as described forexample 32.

MS (ESI) m/z: 580 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 7.99 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.37(1H, d, J=8.1 Hz), 7.28-7.18 (2H, m), 7.12 (1H, t, J=7.5 Hz), 7.09-6.99(4H, m), 6.89 (1H, d, J=2.3 Hz), 6.70 (2H, d, J=9.9 Hz), 5.69 (1H, d,J=6.9 Hz), 4.35-4.30 (1H, m), 3.93-3.86 (5H, m), 3.78 (2H, t, J=6.5 Hz),3.71-3.65 (1H, m), 3.62-3.55 (1H, m), 3.03 (1H, t, J=5.4 Hz), 2.94-2.83(4H, m), 1.40-1.35 (1H, m), 0.71-0.65 (2H, m), 0.43-0.38 (2H, m).

Example 373-(3-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pentan-2-yloxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 37 was prepared in an analogous fashion as described forexample 32.

MS (ESI) m/z: 596 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.01 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.37(1H, d, J=8.1 Hz), 7.21 (2H, t, J=7.6 Hz), 7.12 (1H, t, J=7.5 Hz),7.08-6.98 (4H, m), 6.88 (1H, d, J=2.3 Hz), 6.74 (1H, s), 6.69 (1H, s),5.68 (1H, d, J=6.9 Hz), 4.41-4.29 (2H, m), 3.85 (3H, s), 3.78 (2H, t,J=6.6 Hz), 3.71-3.65 (1H, m), 3.62-3.55 (1H, m), 3.10 (1H, t, J=5.4 Hz),2.93-2.83 (4H, m), 1.86-1.50 (4H, m), 1.35 (3H, dd, J=6.1, 2.0 Hz),1.03-0.94 (3H, m).

Example 38(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-(2-hydroxyethoxy)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 38 was prepared in an analogous fashion as described forexample 32.

MS (ESI) m/z: 570 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.06 (1H, s), 7.58 (1H, d, J=7.9 Hz), 7.37(1H, d, J=8.1 Hz), 7.25-7.18 (2H, m), 7.14-6.97 (5H, m), 6.91 (1H, d,J=2.3 Hz), 6.69 (2H, d, J=9.4 Hz), 5.71 (1H, d, J=6.9 Hz), 4.36-4.30(1H, m), 4.19 (2H, t, J=4.5 Hz), 3.98 (2H, t, J=4.3 Hz), 3.87 (3H, s),3.78 (2H, t, J=6.5 Hz), 3.71-3.55 (2H, m), 3.07 (1H, s), 2.97-2.82 (4H,m), 2.58 (1H, s).

Example 39(R)-9-(2-(dimethylamino)ethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 39 was prepared in an analogous fashion as described forexample 32.

¹H NMR δ (ppm) (CHCl₃-d): 8.47 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.38(1H, d, J=8.0 Hz), 7.31-7.15 (2H, m), 7.15-6.98 (5H, m), 6.95 (1H, s),6.68 (1H, s), 6.60 (1H, s), 5.77 (1H, s), 4.46-4.18 (1H, m), 4.22 (2H,t, J=6.1 Hz), 3.86 (3H, s), 3.78 (2H, t, J=6.6 Hz), 3.74-3.57 (6H, m),2.43 (6H, s).

Example 409-(2,3-dihydroxypropoxy)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl9-(allyloxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Compound 40a was prepared in an analogous fashion as described forcompound 32b

¹H NMR δ (ppm) (CHCl₃-d): 7.48 (1H, dd, J=4.1, 2.3 Hz), 7.15-7.10 (3H,m), 6.89 (1H, s), 6.71 (1H, s), 6.18-6.07 (1H, m), 5.48 (1H, dd, J=17.2,1.7 Hz), 5.32 (1H, dd, J=10.5, 1.5 Hz), 4.67 (2H, dt, J=5.4, 1.5 Hz),4.19 (2H, q, J=7.1 Hz), 3.94 (2H, t, J=6.60 Hz), 3.89 (3H, s), 2.94 (2H,t, J=6.6 Hz), 1.21 (3H, t, J=7.1 Hz).

(b). ethyl9-(2,3-dihydroxypropoxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Osmium tetraoxide (1.5 mg) was added to a solution of intermediate 40a(100 mg,) and N-methylmorpholine N-oxide (42 mg) in a 1:1 mixture ofwater and THF (2 ml). The reaction tube was sealed and stirred at roomtemperature for 16 hours. The crude product was extracted into DCM (3×)and the combined organics were passed through a hydrophobic frit andpurified by chromatography on silica gel eluting with DCM and increasingamounts of methanol.

Yield: 45 mg

MS (ESI) m/z: 444 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 7.48 (1H, t, J=3.3 Hz), 7.16-7.11 (3H, m),6.91 (1H, s), 6.72 (1H, s), 4.26-4.09 (5H, m), 3.94 (2H, t, J=6.5 Hz),3.96-3.75 (5H, m), 3.15 (1H, s), 2.95 (2H, t, J=6.6 Hz), 2.45 (1H, s),1.22 (3H, t, J=7.1 Hz).

(c).9-(2,3-dihydroxypropoxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

Sodium hydroxide (12 mg) in water (0.2 ml) was added to a solution ofintermediate 40b (44 mg) in ethanol (2 ml). The reaction mixture washeated to 80° C. for 3 hours. The solvents were removed under vacuum andthe residue redissolved in water, washing with diethyl ether (2×). Theaqueous layer was acidified to ˜pH 4 with a aqueous 4M HCl solution andthe product extracted into ethyl acetate (3×). The combined organicswere passed through a hydrophobic frit and concentrated under vacuum togive the product as a yellow solid.

Yield: 36 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.49 (1H, dd, J=4.9, 1.5 Hz), 7.18-7.11 (3H,m), 6.95 (1H, s), 6.72 (1H, s), 4.25-4.19 (1H, m), 4.14-4.08 (2H, m),3.94 (2H, t, J=6.6 Hz), 3.87 (3H, s), 3.84 (2H, dd, J=7.1, 3.7 Hz), 2.95(2H, t, J=6.6 Hz).

(d.)9-(2,3-dihydroxypropoxy)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23 mg) wasadded to a solution of intermediate 40c (33 mg), diisopropylethylamine(42 μl), 1-hydroxybenzotriazole (16 mg), and D-tryptophanol (18 mg) indry DMF (1 ml). The mixture was stirred at room temperature for 5 hours.The solvent was removed under vacuum and water was added, extractingwith ethyl acetate (3×). The combined organic layers were passed througha hydrophobic frit and concentrated to dryness under vacuum. The cruderesidue was redissolved in MeCN and purified by preparative HPLC elutingwith acetonitrile and water to give the product as an off white solid.

Yield: 28 mg

MS (ESI) m/z: 588 (M+H)⁺.

¹H NMR δ (ppm) (DMSO-d₆): 10.77 (1H, s), 7.68 (1H, t, J=3.3 Hz), 7.61(1H, d, J=7.9 Hz), 7.32 (1H, d, J=8.1 Hz), 7.17-7.11 (3H, m), 7.09-6.95(4H, m), 6.90 (2H, s), 4.97 (1H, d, J=5.1 Hz), 4.70 (2H, q, J=6.1 Hz),4.15-4.09 (1H, m), 4.08-3.95 (1H, m), 3.92-3.89 (1H, m), 3.87-3.81 (3H,m), 3.78 (3H, s), 3.50-3.40 (2H, m), 3.42-3.38 (1H, m), 3.35-3.28 (1H,m), 2.94-2.88 (3H, m), 2.82-2.77 (1H, m).

Example 419-(2,3-dihydroxypropoxy)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl9-(allyloxy)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Example 41 was prepared in an analogous fashion as described for example32 starting from compound 40a.

¹H NMR δ (ppm) (CHCl₃-d): 7.48 (1H, dd, J=4.1, 2.3 Hz), 7.15-7.10 (3H,m), 6.89 (1H, s), 6.71 (1H, s), 6.18-6.07 (1H, m), 5.48 (1H, dd, J=17.2,1.7 Hz), 5.32 (1H, dd, J=10.5, 1.5 Hz), 4.67 (2H, dt, J=5.4, 1.5 Hz),4.19 (2H, q, J=7.1 Hz), 3.94 (2H, t, J=6.60 Hz), 3.89 (3H, s), 2.94 (2H,t, J=6.6 Hz), 1.21 (3H, t, J=7.1 Hz).

Example 42(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). 3-Methoxy-4-nitro-benzaldehyde

A mixture of 3-hydroxy-4-nitrobenzaldehyde (51.3 g), iodomethane (38.3ml) and potassium carbonate (85 g) in DMF (250 ml) was stirred at 60° C.for 1 h. The reaction mixture was cooled to room temperature and pouredinto water. The solids were collected by filtration and dried in vacuo(50° C.).

Yield: 49.7 g.

(b). 4-Amino-3-methoxy-benzaldyde

Iron (112 g) was added to a mixture of the product of example 42a (49.7g) and ammonium chloride (103 g) in ethanol (500 ml) and water (500 ml).After stirring with a mechanical stirrer at 78° C. for 2 h, the reactionmixture was cooled to room temperature and extracted with diethyl ether.The combined organic layers were concentrated in vacuo and water wasadded to the residue. The solids were collected by filtration and driedin vacuo (50° C.).

Yield: 38.3 g.

(c). 4-Bromo-3-methoxy-benzaldehyde

A solution of the product of example 42b (38.3 g) in acetonitrile (600ml) was added dropwise to a mixture of n-butyl nitrite (43.1 ml) andcopper(I) bromide (63.6 g) in acetonitrile (1300 ml). After stirring for18 h at room temperature, the reaction mixture was diluted with ethylacetate and washed with an aqueous 1M HCl solution. The organic layerwas separated and washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel in heptane/ethyl acetate [1:1 (v/v)].

Yield: 27.4 g.

MS (ESI) m/z: 215,217 (M+H)⁺.

(d). 1-Bromo-2-methoxy-4-((E)-2-nitro-vinyl)-benzene

A mixture of the product of example 42c (27.4 g), ammonium acetate (10.8g) and nitromethane (35 ml) in acetic acid (125 ml) was stirred at 80°C. for 18 h. The reaction mixture was cooled to room temperature andpoured into water. The solids were collected by filtration and dissolvedin dichloromethane. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated in vacuo.

Yield: 29.8 g.

(e). 2-(4-Bromo-3-methoxy-phenyl)-ethylamine

At 0° C. and under a nitrogen atmosphere a solution of borane-THFcomplex (262 ml 1M) was added dropwise to a solution of the product ofexample 42d (15 g) in THF (250 ml). After the addition, the icebath wasremoved. Sodium borohydride (0.11 g) was added (a slight exothermicreaction took place). After stirring for 18 h at 65° C. under a nitrogenatmosphere, the reaction mixture was cooled to room temperature andpoured into an aqueous 2M HCl solution. After stirring for 1.5 h at 70°C., the reaction mixture was cooled to room temperature and extractedtwice with diethyl ether. The aqueous layer was made basic with solidsodium hydroxide H until pH=10 and extracted three times with ethylacetate. The combined organic layers were washed with brine, dried(MgSO₄), filtered and concentrated in vacuo.

MS (ESI) m/z: 230,232 (M+H)⁺.

(f). N-(4-bromo-3-methoxyphenethyl)acetamide

Compound 42e (15.6 g) was dissolved in DCM (200 ml). DIPEA (20.31 ml)was added and acetyl chloride (5.01 ml) was added dropwise at 0° C.under nitrogen atmosphere. The reaction mixture was allowed to warm upto ambient temperature over 1 hour. The reaction mixture was washedsequentially with a aqueous 0.2M HCl solution, a aqueous saturatedNaHCO₃ solution, water and brine, dried (MgSO₄) and filtered. Thesolvent were removed under vacuum to yield a pale yellow oil which wastriturated with diethylether. The solid was filtered and dried toconstant mass.

Yield: 14.75 g

(g). 7-bromo-6-methoxy-1-methyl-3,4-dihydroisoquinoline

Phosphorus oxychloride (7.26 g) was added to a solution of compound 42f(5.42 g) in toluene (33 ml) before heating to 110° C. for 2 hours. Thesolution was allowed to cool to ambient temperature before beingconcentrated to dryness under vacuum to give a yellow residue. The cruderesidue was triturated with toluene (2×50 ml) to give product the as apale yellow solid

Yield: 8.13 g

¹H NMR δ (ppm) (DMSO-d): 8.27 (1H, s), 7.34 (1H, s), 4.04 (3H, s),3.85-3.77 (2H, m), 3.15-3.06 (2H, m), 2.79 (3H, s).

(h). ethyl9-bromo-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Ethyl-3-bromopyruvate (0.87 g) was added to a solution of intermediate42g (1.0 g), potassium carbonate (5.0 g) and triethylamine (0.72 g) inacetonitrile (20 ml) and then heated to 100° C. for 2 hours. Thereaction mixture was allowed to cool to ambient temperature and was thenfiltered through celite, washing the filter pad thoroughly withacetonitrile. The dark filtrate was concentrated to dryness to give anoil which was partitioned between ethyl acetate (20 ml) and water (20ml). The organic phase was separated and concentrated to dryness undervacuum to give the product as a pale green oil

Yield: 250 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.73 (1H, s), 7.31 (1H, d, J=1.62 Hz),6.84-6.81 (1H, m), 6.79-6.74 (1H, m), 4.42-4.28 (2H, m), 4.15-4.07 (2H,m), 3.97-3.90 (3H, m), 3.09-3.01 (2H, m), 1.43-1.32 (3H, m).

(i). ethyl8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

[1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (44 mg) wasadded to a degassed solution of intermediate 42h (200 mg),pyridine-3-boronic acid (104 mg,) and potassium carbonate (156 mg) in9:1 dioxane:water (5.3 ml). The reaction mixture was degassed for 15minutes with nitrogen before sealing and then heating to 85° C. for 90minutes. The solvents were removed under vacuum and the residue obtainedwas partitioned between water and ethyl acetate. The organic phase wasconcentrated to dryness under vacuum to give a dark oil that waspurified by chromatography on silica gel eluting with petrol andincreasing amounts of ethyl acetate to give the product as a colourlessoil.

Yield: 205 mg

¹H NMR δ (ppm) (CHCl₃-d): 8.81-8.79 (1H, m), 8.58 (1H, dd, J=4.84, 1.67Hz), 7.88-7.84 (1H, m), 7.63-7.39 (1H, m), 7.38-7.32 (2H, m), 6.85 (2H,d, J=1.97 Hz), 4.38-4.25 (2H, m), 4.17-4.08 (2H, m), 3.84 (3H, s),3.17-3.10 (2H, m), 1.36 (3H, t, J=7.12 Hz).

(j).8-methoxy-9-(Pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A aqueous 2N sodium hydroxide solution (1 ml) was added to a solution ofintermediate 42i (190 mg) in ethanol (3 ml) and the mixture was thenheated to 75° C. for three hours. The solvents were removed under vacuumand the residue obtained was suspended in water (5 ml) and the pH wasadjusted to pH 1 with a aqueous 1 N HCl solution. A solid precipitatewas filtered, washed with water and dried in air to give the product asan off white solid.

Yield: 148 mg

¹H NMR δ (ppm) (DMSO-d₆): 9.10 (1H, d, J=2.00 Hz), 8.85 (1H, d, J=5.53Hz), 8.70 (1H, d, J=8.14 Hz), 8.05 (1H, dd, J=8.13, 5.53 Hz), 7.87 (1H,s), 7.49 (1H, d, J=1.65 Hz), 7.22 (1H, s), 6.94 (1H, d, J=1.66 Hz),4.22-4.15 (2H, m), 3.92-3.87 (3H, m), 3.15 (2H, t, J=6.49 Hz).

(k).(R)—N-(1-(tert-butyldimethylsilyloxy)-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg) wasadded to a solution of intermediate 42j (140 mg), 1-hydroxybenzotriazole(64 mg) and diisopropylamine (146 mg) in DMF (1.5 ml). The mixture wasstirred for 5 minutes before the addition of 6b (133 mg), stirring for afurther 18 hours. The reaction mixture was partitioned between ethylacetate and water and the aqueous phase was re-extracted with ethylacetate. The combined organic layers were washed with water and thenconcentrated to dryness under vacuum to give an orange oil. The crudeoil was purified by chromatography on silica gel eluting with petrol andincreasing amounts of ethyl acetate to give the product as a white foam.

Yield: 165 mg

¹H NMR δ (ppm) (CHCl₃-d): 8.79 (1H, d, J=2.21 Hz), 8.59 (1H, dd, J=4.82,1.70 Hz), 8.07 (1H, s), 7.89-7.81 (2H, m), 7.38-7.34 (3H, m), 7.19-7.08(4H, m), 6.83 (1H, s), 6.40 (1H, d, J=1.76 Hz), 6.12 (1H, d, J=8.52 Hz),4.47 (1H, dd, J=8.58, 5.31 Hz), 4.15-4.07 (2H, m), 3.84 (3H, s), 3.71(1H, dd, J=9.85, 2.99 Hz), 3.57 (1H, dd, J=9.86, 5.40 Hz), 3.22-3.05(4H, m), 0.97 (9H, d, J=1.44 Hz), 0.08 (6H, d, J=7.63 Hz).

(l).(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Palladium (II)acetate (1.9 mg) was added to a degassed solution ofintermediate 42k (50 mg), 3-fluoroiodobenzene (26.0 mg), cesiumcarbonate (58.6 mg) and triphenylphosphine (4.32 mg) in dioxane (3 ml)and the mixture was degassed with nitrogen for a further 15 minutes. Thereaction tube was sealed and then heated to 95° C. for 18 hours. Thereaction was determined to be incomplete, hence a further aliquot ofpalladium (II)acetate (1.9 mg), triphenylphosphine (4.32 mg) and3-fluoroiodobenzene (26.0 mg) were added. The mixture was degassed withnitrogen for 15 minutes, sealed and then heated to 95° C. for 4 hours.The solvents were removed under vacuum and the residue obtained waspartitioned between ethyl acetate and water. The aqueous phase wasre-extracted with ethyl acetate and the combined organic layers werewashed with water and then concentrated to dryness giving a dark brownoil. The oil was redissolved in THF (1 ml) before the addition oftetrabutylammonium fluoride in THF (0.3 ml), stirring for 2 hours. Thesolvents were removed under vacuum to give a dark oil that was purifiedby preparative HPLC eluting with acetonitrile and water to give thetarget compound as a off white solid.

Yield: 3.5 mg

¹H NMR δ (ppm) (CHCl₃-d): 8.81 (1H, s), 8.61 (1H, s), 8.13 (1H, s), 7.89(1H, d, J=7.90 Hz), 7.61-7.57 (1H, m), 7.43-7.31 (3H, m), 7.16-7.00 (6H,m), 6.93 (1H, d, J=2.23 Hz), 6.82 (1H, s), 6.59 (1H, s), 5.77 (1H, d,J=6.82 Hz), 4.35-4.29 (1H, m), 3.90-3.78 (5H, m), 3.69 (1H, dd, J=10.97,3.63 Hz), 3.61 (1H, dd, J=10.97, 6.03 Hz), 3.04-2.83 (4H, m), 2.61 (1H,s).

Example 43(R)-9-ethyl-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl8-methoxy-9-vinyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Tetrakis(triphenylphosphine)palladium(0) (17 mg) was added to a degassedsolution of intermediate 42h (53 mg), vinylboronic acid (41 μl) andpotassium carbonate (37 mg) in a 10:1 mixture of DME:water (2 ml). Themixture was degassed by gently bubbling through nitrogen for a further30 minutes before sealing under nitrogen and then heating to 90° C. for18 hours. The reaction was allowed to cool to ambient temperature thenwater was added, extracting with ethyl acetate (3×). The combinedorganic layers were passed through a hydrophobic frit and concentratedunder vacuum to give a dark brown residue. The residue was purified bychromatography on silica gel eluting with petrol and increasing amountsof ethyl acetate to give product the as an orange solid.

Yield: 64 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.63 (1H, s), 7.28 (1H, d, J=1.6 Hz), 7.01(1H, dd, J=17.8, 11.2 Hz), 6.84 (1H, d, J=1.7 Hz), 6.69 (1H, s), 5.77(1H, dd, J=17.7, 1.5 Hz), 5.29 (1H, dd, J=11.1, 1.5 Hz), 4.30 (2H, q,J=7.1 Hz), 4.08 (2H, t, J=6.6 Hz), 3.85 (3H, s), 3.05 (2H, t, J=6.5 Hz),1.35 (3H, t, J=7.1 Hz).

(b). ethyl9-ethyl-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

10% Palladium on carbon (50 mg) was added to a solution of intermediate43a (62 mg) in ethanol (5 ml). The reaction vessel was flushed withnitrogen then charged with hydrogen and stirred for 72 hours. Thereaction mixture was filtered through celite and the solvent was thenremoved under vacuum. The residue was dissolved in diethyl ether andwashed with water (3×). The organic layer was passed through ahydrophobic frit and then concentrated under vacuum. The residue waspurified by chromatography on silica gel eluting with petrol andincreasing amounts of ethyl acetate to give the product as a colourlessoil/solid.

Yield: 57 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.33 (1H, s), 7.27 (1H, d, J=1.7 Hz), 6.80(1H, d, J=1.7 Hz), 6.66 (1H, s), 4.29 (2H, q, J=7.1 Hz), 4.07 (2H, t,J=6.6 Hz), 3.83 (3H, s), 3.03 (2H, t, J=6.6 Hz), 2.63 (2H, q, J=7.5 Hz),1.35 (3H, t, J=7.1 Hz), 1.21 (3H, t, J=7.5 Hz).

(c). ethyl9-ethyl-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Palladium (II)acetate (4 mg) was added to a degassed solution ofintermediate 43b (57 mg), triphenylphosphine (10 mg),1-fluoro-3-iodobenzene (22 μl) and cesium carbonate (124 mg) in dioxane(2 ml). The mixture was further degassed by bubbling through a gentlestream of nitrogen for 30 minutes. The reaction tube was sealed undernitrogen and then heated to 90° C. for 16 hours. LC-MS analysisindicated the reaction was only ˜50% complete, hence the mixture wasdegassed with nitrogen for 15 minutes before the addition a furtheraliquot of 1-fluoro-3-iodobenzene (22 μl) and palladium (II)acetate (4mg). The mixture was degassed for a further 30 minutes before sealingunder nitrogen and heating to 100° C. for 24 hours. Water was added andthe product was extracted into ethyl acetate (3×). The combined organiclayers were passed through a hydrophobic frit and concentrated todryness under vacuum. The residue was purified by chromatography onsilica gel eluting with petrol and increasing amounts of ethyl acetateto give the product as an off white solid.

Yield: 48 mg

¹H NMR δ (ppm) (CHCl₃-d): 7.43-7.39 (2H, m), 7.19 (1H, dt, J=7.7, 1.2Hz), 7.15-7.08 (2H, m), 6.93 (1H, s), 6.66 (1H, s), 4.16 (2H, q, J=7.1Hz), 3.87 (2H, t, J=6.5 Hz), 3.84 (3H, s), 2.96 (2H, t, J=6.4 Hz), 2.66(2H, q, J=7.5 Hz), 1.26-1.15 (6H, m).

(d).9-ethyl-3-(3-fluorophenyl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

Sodium hydroxide (14 mg) in water (0.5 ml) was added to a solution ofintermediate 43c (47 mg) in ethanol (5 ml) and the mixture heated to 80°C. for 3 hours. The solvents were removed under vacuum and the residueobtained was redissolved in water (10 ml), washing with diethyl ether.The aqueous phase was acidified to ˜pH 4 with a aqueous 4M HCl solutionand then extracted with DCM (3×). The combined organic layers werepassed through a hydrophobic frit and concentrated to dryness undervacuum to the give product as an off white solid.

Yield: 42 mg

¹H NMR δ (ppm) (CHCl₃-d): 11.00 (1H, s), 7.45-7.37 (2H, m), 7.18 (1H, d,J=7.7 Hz), 7.15-7.07 (2H, m), 6.96 (1H, s), 6.66 (1H, s), 3.91-3.81 (5H,m), 2.96 (2H, t, J=6.4 Hz), 2.65 (2H, dd, J=15.0, 7.5 Hz), 1.22 (3H, t,J=7.5 Hz).

(e).(R)-9-ethyl-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg) wasadded to a solution of intermediate 43d (40 mg), diisopropylethylamine(58 μl), 1-hydroxybenzotriazole (22 mg), and D-tryptophanol (25 mg) indry DMF (1 ml), stirring for 70 hours at room temperature. The solventswere removed under vacuum and the residue obtained was partitionedbetween water and ethyl acetate. The aqueous phase was re-extracted withethyl acetate (2×) and the combined organic layers were passed through ahydrophobic frit and concentrated to dryness under vacuum. The cruderesidue was redissolved in MeCN and purified by preparative HPLC elutingwith acetronitrile and water to give the target compound as an off whitesolid

Yield: 27 mg

MS (ESI) m/z: 538 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.04 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.37(1H, d, J=8.1 Hz), 7.31 (1H, s), 7.27-7.19 (2H, m), 7.13 (1H, t, J=7.5Hz), 7.08-6.96 (3H, m), 6.91 (1H, d, J=2.3 Hz), 6.65 (2H, d, J=8.3 Hz),5.73 (1H, d, J=6.8 Hz), 4.35-4.28 (1H, m), 3.83 (3H, s), 3.78 (2H, t,J=6.5 Hz), 3.71-3.54 (2H, m), 3.16 (1H, s), 2.98-2.82 (4H, m), 2.66 (2H,q, J=7.5 Hz), 1.23 (3H, t, J=7.5 Hz).

Example 443-(3-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(3-methylbutan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 44 was prepared in an analogous fashion as described forexample 43.

¹H NMR δ (ppm) (CHCl₃-d): 8.00 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.37(1H, d, J=8.1 Hz), 7.31 (1H, s), 7.24-7.19 (2H, m), 7.13 (1H, t, J=7.5Hz), 7.07-6.97 (3H, m), 6.90 (1H, d, J=2.3 Hz), 6.72 (1H, s), 6.65 (1H,s), 5.72 (1H, d, J=6.9 Hz), 4.36-4.29 (1H, m), 3.83-3.74 (5H, m),3.72-3.57 (2H, m), 3.10 (1H, t, J=5.5 Hz), 2.99-2.83 (5H, m), 1.89-1.82(1H, m), 1.21 (3H, dd, J=7.1, 3.0 Hz), 0.96 (3H, dd, J=6.7, 2.6 Hz),0.81 (3H, dd, J=6.7, 3.0 Hz).

Example 45(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 45 was prepared in an analogous fashion as described forexample 43, skipping reaction b

¹H NMR δ (ppm) (CHCl₃-d): 8.11 (1H, s), 7.56 (1H, d, J=7.89 Hz), 7.35(1H, d, J=8.83 Hz), 6.87 (1H, d, J=2.27 Hz), 6.72 (1H, s), 6.66 (1H, s),6.29 (1H, s), 5.71 (1H, d, J=6.88 Hz), 4.36-4.27 (1H, m), 3.86-3.73 (5H,m), 3.66 (1H, d, J=10.96), 3.58 (1H, dd, J=10.94, 5.88 Hz), 3.16 (1H,s), 2.98-2.79 (4H, m), 1.97 (3H, s), 1.85 (3H, s)

Example 46(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(3-methylbut-2-en-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 46 was prepared in an analogous fashion as described forexample 44, skipping reaction b.

¹H NMR δ (ppm) (CHCl₃-d): 8.02 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.37(1H, d, J=8.1 Hz), 7.24-7.10 (4H, m), 7.06-6.98 (3H, m), 6.92 (1H, d,J=2.3 Hz), 6.69 (1H, s), 6.58 (1H, s), 5.73 (1H, d, J=6.8 Hz), 4.32-4.27(1H, m), 3.82-3.78 (5H, m), 3.70-3.56 (2H, m), 3.20-3.10 (1H, s),2.97-2.82 (4H, m), 1.94 (3H, s), 1.87 (3H, s), 1.55 (3H, s)

Example 47(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

A mixture of compound 42h (105 mg), morpholine (39 μl), xantphos (35mg), palladium (II) acetate (6.7 mg) and sodium carbonate (48 mg) intoluene (2 ml) was saturated with carbon monoxide by bubbling gasthrough it for 20 minutes. The mixture was then heated at 80° C.overnight. The reaction mixture was diluted with water and the extractedwith ethyl acetate (3×). The combined organic layers were passed througha hydrophobic frit and concentrated in vacuo. The residue was purifiedby chromatography on silica gel eluting with DCM containing increasingamounts of methanol.

Yield: 90 mg

(b). ethyl3-(3-fluorophenyl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Palladium (II)acetate (5.2 mg) was added to a degassed solution ofintermediate 47a (88 mg), triphenylphosphine (12 mg),1-fluoro-3-iodobenzene (27 μl) and cesium carbonate (150 mg) in dioxane(2 ml). The mixture was further degassed by bubbling through a gentlestream of nitrogen for 30 minutes. The reaction tube was sealed undernitrogen and then heated to 80° C. for 16 hours. LC-MS analysisindicated the reaction was ˜50% complete, hence the mixture was degassedwith nitrogen for 15 minutes before the addition a further aliquot of1-fluoro-3-iodobenzene (22 μl) and palladium (II)acetate (4 mg). Themixture was degassed for a further 30 minutes before sealing undernitrogen and heating to 80° C. for 4 hours. Water was added and theproduct was extracted into ethyl acetate (3×). The combined organiclayers were passed through a hydrophobic frit and concentrated todryness under vacuum. The residue was purified by chromatography onsilica gel eluting with petrol and increasing amounts of ethyl acetateto give the product, as an off white solid.

Yield: 48 mg

(c).3-(3-fluorophenyl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A aqueous 2N sodium hydroxide solution (0.5 ml) was added to a solutionof intermediate 47b (31 mg) in ethanol (2 ml) and the mixture heated to50° C. for 18 hours. The reaction mixture was acidified with a aqueoussolution of 2M HCl and was extracted with ethyl acetate. The organiclayer was washed with water and dried by passing through a hydrophobicfrit and concentrated in vacuo, to yield an off-white powder.

Yield: 29.6 mg

(d).(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg) wasadded to a solution of intermediate 47c (30 mg), triethylamine (27 μl),1-hydroxybenzotriazole (9.3 mg), and D-tryptophanol (15 mg) in dry DMF(1 ml), stirring for 70 hours at room temperature. The solvents wereremoved under vacuum and the residue obtained was partitioned betweenwater and ethyl acetate. The aqueous phase was re-extracted with ethylacetate (2×) and the combined organics were passed through a hydrophobicfrit and concentrated to dryness under vacuum. The residue was purifiedby chromatography on silica gel eluting with DCM and increasing amountsof methanol (max. 10%). The pure fractions were collected, yielding inthe desired product as an off-white solid.

Yield: 17 mg

¹H NMR δ (ppm) (CHCl₃-d): 8.14 (1H, s), 7.59 (1H, d, J=7.86 Hz),7.42-7.35 (2H, m), 7.21-7.10 (3H, m), 7.09-7.00 (4H, m), 6.94 (1H, s),6.73 (1H, s), 6.58 (1H, s), 5.80-5.69 (1H, m), 4.31 (1H, s), 3.89-3.74(6H, m), 3.68 (2H, s), 3.62 (1H, s), 3.31 (2H, s), 3.18 (1H, d,J=14.81), 3.02-2.83 (4H, m)

Example 48(R)-3-(3-fluorophenyl)-N2-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-N9,N9-dimethyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2,9-dicarboxamide

Compound 48 was prepared in an analogous fashion as described forexample 47.

¹H NMR δ (ppm) (CHCl₃-d): 8.16 (1H, s), 7.58 (1H, d, J=7.89 Hz),7.40-7.31 (2H, m), 7.21 (1H, s), 7.15-6.99 (4H, m), 6.94 (1H, d, J=2.29Hz), 6.73-6.68 (1H, m), 6.53 (1H, s), 5.77 (1H, d, J=6.61 Hz), 4.30 (1H,t, J=6.40 Hz), 3.86-3.75 (4H, m), 3.72-3.65 (2H, m), 3.63-3.56 (1H, m),3.25 (1H, s), 3.20-3.14 (3H, m), 2.99-2.82 (6H, m)

Example 49(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). ethyl9-isopropoxy-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 2b (1 g) in dioxane (20 ml) were added2-bromothiophene (775 mg), triphenylphosphine (180 mg) and cesiumcarbonate (2.06 g). The reaction mixture was degassed for 10 minutesunder N₂. Then palladium(II)acetate (80 mg) was added and the mixturewas degassed for another 10 minutes under N₂. The reactant was heatedunder reflux for 20 hours. The mixture was cooled to room temperature,diluted with ethyl acetate and filtered. The filtrate was washed withwater and brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby chromatography on silica gel (petrol:ethyl acetate=10:1-6:1) to givethe desired product

Yield: 550 mg

MS (ESI) m/z: 412 (M+H)⁺.

(b). ethyl9-hydroxy-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 49a (282 mg) in DCM (7 ml) was added aluminiumchloride (365 mg) at 0° C. The reaction mixture was stirred at 0° C. for2 hours. The reaction mixture was washed with water and DCM phase wasdried over anhydrous Na₂SO₄, filtered and concentrated to give thedesired compound the desired product.

Yield: 230 mg

MS (ESI) m/z: 370 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.99 (s, 1H), 7.74-7.75 (m, 1H), 7.20-7.22 (m,1H), 7.17-7.19 (m, 1H), 7.05 (s, 1H), 6.86 (s, 1H), 6.77 (s, 1H),4.04-4.09 (m, 2H), 3.87 (t, 2H, J=6.6 Hz), 3.78 (s, 3H), 2.89 (t, 2H,J=6.6 Hz), 1.13 (t, 2H, J=7.0 Hz).

(c). ethyl8-methoxy-3-(thiophen-2-yl)-9-(trifluoromethylsulfonyloxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 49b (20 mg) in DCM (2 ml) were addedtrifluoromethanesulfonic anhydride (16.8 mg) and pyridine (6.4 mg). Thereaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was washed with water, and the DCM phase was dried overanhydrous Na₂SO₄, filtered and concentrated to give the desiredcompound.

Yield: 23 mg

MS (ESI) m/z: 502 (M+H)⁺.

1HNMR (CDCl3 400 MHz) 7.39 (s, 1H) 7.26 (s, 1H), 7.08 (s, 1H), 7.01 (s,1H), 6.92 (s, 1H), 6.87 (s, 1H), 4.19 (m, 2H), 3.98 (t, 2H, J=6.56 Hz),3.92 (s, 3H), 3.01 (t, 2H, J=6.63 Hz), 1.29 (d, 5H, J=6.94 Hz), 1.21 (t,4H, J=7.17 Hz).

(d). ethyl8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 49c (40 mg) in dioxane/water (5 ml/0.5 ml) wasadded pyrimidin-5-ylboronic acid (11.8 mg),(tetrakis(triphenylphosphine)palladium(0) (11 mg) and Na₂CO₃ (10 mg).The reaction mixture was heated to reflux for 2 hours. The mixture wascooled to room temperature and diluted with ethyl acetate and filtered.The filtrate was washed with water and brine. The ethyl acetate layerwas dried over anhydrous Na₂SO₄, filtered and concentrated to give thecrude product which was purified by chromatography on silica gel(petrol:ethyl acetate=6:1→3:1) to give the desired product.

Yield: 30 mg

MS (ESI) m/z: 432 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 9.18 (s, 1H), 8.94 (s, 2H), 7.64-7.69 (m, 6H),7.53-7.57 (m, 4H), 7.44-7.48 (m, 8H), 7.25 (s, 1H), 7.13-7.15 (m, 2H),6.97 (s, 1H), 6.86 (s, 1H), 4.15-4.21 (m, 2H), 4.00 (t, 2H, J=6.6 Hz),3.86 (s, 3H), 3.07 (t, 2H, J=6.5 Hz), 1.22 (t, 3H, J=7.1 Hz).

(e).8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

To a solution of compound 49d (25 mg) in methanol (2 ml) was addedaqueous sodium hydroxide solution (0.5 ml, wt 9%). The reaction mixturewas heated to 40° C. for 2 hours. The reaction mixture was acidifiedwith a aqueous 2N HCl solution (3 ml) to pH=2 and extracted with ethylacetate, the organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated to give the desired compound.

Yield: 14 mg

MS (ESI) m/z: 404 (M+H)⁺.

(f).(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

To a solution of compound 49e (14 mg) in DMF (2 ml) were addedtryptophanol (9 mg), triethylamine (12 mg) and HATU (15 mg). Then thereaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was diluted with water and extracted into ethylacetate. The organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product which was purified by preparativeHPLC, with acetonitrile and water as eluens to give the desired product.

Yield: 11 mg

LCMS (EI) (M+H)⁺576

¹H NMR δ (ppm) (CHCl₃-d): 9.20 (s, 1H), 8.98 (s, 2H), 8.05 (s, 1H), 7.55(d, 1H, J=7.8 Hz), 7.46 (s, 1H), 7.38 (m, 2H), 7.08-7.18 (m, 2H),6.94-6.95 (m, 3H), 6.82 (d, 2H, J=9.1 Hz), 5.91 (d, 1H, J=6.9 Hz), 4.33(s, 1H), 3.86 (s, 2H), 3.85 (s, 3H), 3.66-3.70 (m, 1H), 3.55-3.59 (m,1H), 3.04 (t, 2H, J=6.5 Hz), 2.77-2.91 (m, 2H)

Example 50(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 50 was prepared in analogous fashion as described for example49. MS (ESI) m/z: 588 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 9.23 (s, 1H), 9.00 (s, 2H), 8.14 (s, 1H), 7.58(d, 1H, J=7.2 Hz), 7.42 (s, 1H), 7.36 (d, 1H, J=7.4 Hz), 7.03-7.16 (m,5H), 6.95 (s, 1H), 6.85 (s, 1H), 6.60 (s, 1H), 5.81 (d, 1H, J=6.3 Hz),4.31-4.32 (m, 1H), 3.86 (s, 3H), 3.85 (s, 2H), 3.69-3.72 (m, 1H),3.59-3.64 (m, 1H), 3.03 (t, 2H, J=6.3 Hz), 2.85-2.99 (m, 2H).

Example 51(R)-9-(2-(dimethylamino)pyrimidin-5-yl)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 51 was prepared in an analogous fashion as described forexample 49. MS (ESI) m/z: 631 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 9.24 (s, 1H), 8.85 (s, 2H), 7.58 (d, 1H, J=7.4Hz), 7.38 (d, 1H, J=8.3 Hz), 7.29-7.33 (m, 2H), 7.03-7.15 (m, 6H), 6.81(s, 1H), 6.28 (s, 1H), 5.96 (d, 1H, J=4.7 Hz), 4.28 (s, 1H), 3.86 (s,3H), 3.76-3.83 (m, 2H), 3.63-3.67 (m, 2H), 3.43 (s, 6H), 3.03-3.08 (m,1H), 2.99 (t, 2H, J=5.5 Hz), 2.85-2.91 (m, 1H).

Example 52(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 52 was prepared in analogous fashion as described for example49.

MS (ESI) m/z: 590 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.16 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.61(s, 1H), 7.58 (d, 1H, J=8.1 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.20 (t,1HJ=8.0 Hz), 7.13 (t, 1H, J=8.0 Hz), 7.01-7.07 (m, 3H), 6.95 (s, 1H),6.77 (s, 1H), 6.66 (s, 1H), 5.85 (d, 1H, J=6.8 Hz), 4.33-4.36 (m, 1H),4.02 (s, 3H), 3.92 (s, 3H), 3.81 (t, 2H, J=6.6 Hz), 3.70-3.74 (m, 1H),3.60-3.64 (m, 1H), 2.94-2.99 (m, 3H), 2.85-2.91 (m, 1H).

Example 533-(3-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 53 was prepared in analogous fashion as described for example49.

MS (ESI) m/z: 617 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.20-8.22 (m, 1H), 8.01 (s, 1H), 7.57 (d, 2H,J=5.5 Hz), 7.39 (s, 1H), 7.33 (t, 1H, J=5.4 Hz), 6.97-7.10 (m, 6H), 6.90(s, 1H), 6.79 (s, 1H), 6.59 (s, 1H), 5.72 (d, 1H, J=5.4 Hz), 4.29-4.31(m, 1H), 3.95 (s, 3H), 3.83 (t, 2H, J=5.4 Hz), 3.78 (s, 3H), 3.66-3.69(m, 1H), 3.57-3.61 (m, 1H), 3.14-3.15 (m, 1H), 3.00 (t, 2H, J=6.5 Hz),2.82-3.01 (m, 2H).

Example 54N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-3-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 54 was prepared in analogous fashion as described for example49.

MS (ESI) m/z: 605 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 10.73 (s, 1H), 8.17-8.18 (m, 1H), 7.56-7.67(m, 3H), 7.36 (s, 1H), 7.28 (d, 1H, J=7.6 Hz), 7.11-7.13 (m, 1H),7.02-7.06 (m, 5H), 6.92-6.98 (m, 1H), 6.84 (s, 1H), 4.03-4.07 (m, 1H),3.89 (t, 2H, J=6.0 Hz), 3.82 (s, 3H), 3.73 (s, 3H), 3.02 (t, 2H, J=6.0Hz (s, 1H), 2.84-2.89 (m, 1H), 2.70-2.75 (m, 1H).

Example 55(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1-methyl-1H-pyrazol-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 55 was prepared in analogous fashion as described for example49.

MS (ESI) m/z: 578 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 10.74 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H),7.78 (s, 1H), 7.65-7.66 (m, 1H), 7.56 (d, 1H, J=8 Hz), 7.29 (d, 1H,J=8.0 Hz), 7.13 (s, 2H), 7.05 (s, 5H), 7.00 (s,), 6.89 (d, 1H, J=8.3Hz), 4.09-4.11 (m, 1H), 3.88 (s, 8H), 3.38-3.42 (m, 2H), 3.28-3.32 (m,2H), 2.98 (t, 2H, J=5.6 Hz), 2.88-2.94 (m, 1H), 2.74-2.79 (m, 1H).

Example 56(R)-9-(2-(dimethylamino)pyrimidin-5-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 56 was prepared in analogous fashion as described for example49.

MS (ESI) m/z: 619 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 10.74 (s, 1H), 8.51 (s, 1H), 7.66 (d, 1H,J=3.6 Hz), 7.56 (d, 1H, J=8.4 Hz), 7.51 (s, 1H), 7.28 (d, 1H, J=7.8 Hz),7.11 (s, 1H), 6.98-7.05 (m, 2H), 6.88-6.94 (m, 2H), 4.05-4.07 (m, 1H),3.86 (t, 2H, J=6.0 Hz), 3.77 (s, 3H), 3.35-3.39 (m, 2H), 3.25-3.29 (m,2H), 3.14 (s, 5H), 2.98 (t, 1H, J=5.7), 2.86-2.90 (m, 1H), 2.71-2.76 (m,1H).

Example 57(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 57 was prepared in analogous fashion as described for example49.

MS (ESI) m/z: 605 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.33 (s, 1H), 8.17 (s, 1H), 7.52-7.55 (m, 2H),7.34-7.39 (m, 2H), 6.013 (s, 1H), 7.28 (s, 1H), 7.07-7.18 (m, 3H),6.89-6.94 (m, 3H), 6.83 (s, 1H), 5.97 (d, 1H, J=7.0 Hz), 4.30-4.39 (m,1H), 4.09 (s, 3H), 3.81-3.85 (m, 8H), 3.66-3.68 (m, 1H), 3.57-3.58 (m,1H), 3.03 (s, 2H), 2.76-2.90 (m, 2H).

Example 58(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(6-methoxypyridin-3-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 58 was prepared in analogous fashion as described for example49.

MS (ESI) m/z: 605 (M+H)⁺.

¹H NMR δ (ppm) (CHCl₃-d): 8.50 (s, 1H), 8.33 (s, 1H), 7.99 (d, 1H, J=6.8Hz), 7.55 (d, 1H, J=6.9 Hz), 7.35-7.44 (m, 3H), 7.08-7.17 (m, 2H), 6.96(d, 3H, J=3.8 Hz), 6.80 (s, 1H), 6.73 (s, 1H), 5.99 (s, 1H), 4.30-4.37(m, 1H), 4.08 (s, 3H), 3.84-3.87 (m, 5H), 3.70 (s, 1H), 3.48-3.70 (m,9H), 3.02 (s, 2H), 2.91-2.95 (m, 1H), 2.80-2.84 (m, 1H).

Example 59(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1H-pyrazol-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 59 was prepared in analogous fashion as described for example49.

¹H NMR δ (ppm) (CHCl₃-d): 8.12 (s, 1H), 8.06 (s, 1H), 7.70 (s, 1H), 7.57(d, 1H, J=7.2 Hz), 7.36-7.39 (m, 2H), 7.20 (t, 1HJ=8 Hz), 7.12 (t, 1H,J=6.9 Hz), 6.92-6.96 (m, 4H), 6.79 (s, 1H), 5.90 (d, 1H, J=7.6 Hz),4.34-4.38 (m, 1H), 3.92 (s, 3H), 3.85 (t, 2H, J=6.4 Hz), 3.67-3.71 (m,1H), 3.56-3.59 (m, 1H), 3.00 (t, 2H, J=6.2 Hz), 2.78-2.92 (m, 2H).

Example 60(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide(a). (Z)-1,2,3-trimethoxy-4-(2-nitrovinyl)benzene

2,3,4-trimethoxybenzaldehyde (20 g) was dissolved in nitromethane (50ml). Ammonium acetate (8.25 g) was added, and the reaction was heated to50° C. for 2 hrs. The solvents were evaporated in vacuo. The orangeresidue was partitioned between water and DCM. The organic layer waswashed with brine, dried over Na₂SO₄ filtered and concentrated in vacuo.

Yield: 26.3 g

(b/c). N-(2,3,4-trimethoxyphenethyl)acetamide

Lithium aluminium hydride, 2.4M in THF (69.7 ml) was diluted withtetrahydrofuran (dry) (400 ml), and heated to 65° C. in a three-neckedflask under a N2 atmosphere. To this hot solution was added dropwise asolution of compound 60a (10 g) in tetrahydrofuran (dry) (150 ml),maintaining a gentle reflux, over the course of 2 hours. After additionwas complete, reflux was continued for 1 h. The reaction mixture wascooled to 0° C. in an ice bath, and then the excess lithium aluminiumhydride quenched by portionwise addition of sodium sulfate decahydrate(53.9 g). After quenching, ˜10 g anhydrous sodium sulfate was added, thereaction mixture stirred for 15 minutes, and then filtered over a Celitepad and the solvents evaporated, yielding 7.7 g clear yellow oil. Theintermediate was dissolved in acetic anhydride (39.4 ml), sodiumbicarbonate (3.51 g) was added and the solution stirred at roomtemperature for 36 hours. The reaction mixture was poured into water,and extracted with DCM twice. The combined organics were washed with aaqueous saturated NaHCO₃ solution, brine, then dried over Na₂SO₄ andconcentrated in vacuo. The product was purified using chromatography onsilica gel, methanol/DCM 1/99>7/93 gradient. The compound slowlycrystallizes on standing.

Yield: 3.97 g

(d). 5,6,7-trimethoxy-1-methyl-3,4-dihydroisoquinoline

To a solution of compound 60c (1.8 g) in toluene (10 ml) was addeddropwise phosphorus oxychloride (0.2 ml) under nitrogen atmosphere at90° C., over a period of 1 hour. The mixture was heated at 120° C. for 2hours and allowed to cool to room temperature overnight. The resultingHCl salt was collected by filtration and washed with ether to give theproduct as a brown solid

Yield: 2.2 g

(e). ethyl7,8,9-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

To a mixture of 63d (2.1 g) and potassium carbonate (3.7 g) inacetonitrile (15 ml) was added dropwise ethylbromopyruvate (1.6 g). Thereaction mixture was refluxed for 2 hours. The reaction was allowed tocool to ambient temperature before a saturated aqueous NaHCO₃ solutionwas added. The aqueous phase was extracted with ethyl acetate twice. Thecombined organic layers were washed with brine. The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel eluting with petrol andincreasing amounts of ethyl acetate. The pure fractions of the desiredproduct were concentrated in vacuo.

Yield: 0.9 g

(f). ethyl7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylate

Palladium (II)acetate (7.5 mg) was added to a degassed solution ofintermediate 60e (150 mg), triphenylphosphine (20 mg), phenylbromide (27μl) and cesium carbonate (200 mg) in dioxane (2 ml). The mixture wasfurther degassed by bubbling through a gentle stream of nitrogen for 30minutes. The reaction tube was sealed under nitrogen and then heated to80° C. for 16 hours. LC-MS analysis indicated the reaction was ˜50%complete, hence the mixture was degassed with nitrogen for 15 minutesbefore the addition a further aliquot of 1-fluoro-3-iodobenzene (22 μl,)and palladium (II)acetate (4 mg). The mixture was degassed for a further30 minutes before sealing under nitrogen and heating to 80° C. for 4hours. Water was added and the product was extracted into ethyl acetate(3×). The combined organic layers were passed through a hydrophobic fritand concentrated to dryness under vacuum. The residue was purified bychromatography on silica gel eluting with heptane and increasing amountsof ethyl acetate.

Yield: 90 mg

(g).7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxylicacid

A aqueous solution of 2M sodium hydroxide (0.75 ml) was added to asolution of intermediate 60f (90 mg) in ethanol (2 ml) and the mixtureheated to 50° C. for 18 hours. The reaction mixture was acidified with aaqueous solution of 2M HCl and was extracted with ethyl acetate. Theorganic layer was washed with water and dried by passing through ahydrophobic frit and concentrated in vacuo, to yield an off-whitepowder.

Yield: 93 mg

(h).(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg) wasadded to a solution of intermediate 60g (93 mg), triethylamine (102 μl),1-hydroxybenzotriazole (34 mg), cesium carbonate (200 mg) andD-tryptophanol (56 mg) in dry DMF (1 ml), stirring for 70 hours at roomtemperature. The solvents were removed under vacuum and the residueobtained was partitioned between water and ethyl acetate. The aqueousphase was re-extracted with ethyl acetate (2×) and the combined organiclayers were passed through a hydrophobic frit and concentrated todryness under vacuum. The residue was purified by chromatography onsilica gel eluting with DCM and increasing amounts of methanol (max.10%). The pure fractions were collected.

Yield: 48 mg

¹H NMR δ (ppm) (CHCl₃-d): 8.04-7.96 (1H, m), 7.53 (1H, m, J=7.90 Hz),7.35-7.1 (8H, m), 6.91 (2H, d, J=8.63 Hz), 6.82 (1H, d, J=2.32 Hz), 5.61(1H, d, J=6.90 Hz), 4.32-4.26 (1H, m), 3.93-3.80 (9H, s), 3.73 (2H, q,J=6.61 Hz), 3.67-3.60 (1H, m), 3.53 (1H, Dt, J=11.00, 5.40 Hz), 3.11(1H, t, J=5.56 Hz)), 3.98-3.88 (2H, m), 2.85-2.71 (2H, m)

Example 61(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 61 was prepared in an analogous fashion as described forexample 60.

¹H NMR δ (ppm) (CHCl₃-d): 8.05 (1H, s), 7.57 (1H, d, J=7.90 Hz),7.39-7.34 (2H, m), 7.2 (1H, m), 7.15-7.09 (1H, m), 6.97-6.88 (5H, m),5.87 (1H, d, J=6.91 Hz), 4.38-4.30 (1H, m), 3.89 (10H, m), 3.80-3.71(2H, m), 3.72-3.64 (1H, m), 3.60-3.52 (1H, Dtm), 3.09 (1H, t, J=5.51Hz)), 2.97-2.74 (4H, m).

Example 62(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 62 was prepared in an analogous fashion as described forexample 60.

¹H NMR δ (ppm) (CHCl₃-d): 8.09-7.99 (1H, m), 7.57 (1H, m, J=7.89 Hz),7.37 (1H, d, J=8.09 Hz), 7.15-7.09 (1H, m), 7.05-6.99 (3H, m), 6.89-6.85(2H, m), 6.81 (1H, s), 5.70 (1H, d, J=6.98 Hz), 4.37-4.29 (1H, m), 3.89(9H, s), 3.78-3.64 (3H, m), 3.59 (1H, Dd, J=10.97, 5.87 Hz), 3.08 (1H,s), 2.96-2.79 (4H, m)

Example 63(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 63 was prepared in an analogous fashion as described forexample 60, but starting from 3,4,5-trimethoxybenzaldehyde.

¹H NMR δ (ppm) (CHCl₃-d): 8.04-7.96 (1H, m), 7.55-7.50 (1H, m), 7.35-7.2(5H, m), 7.19-7.08 (3H, m), 6.85 (1H, d, J=2.30 Hz), 6.52 (1H, s), 5.63(1H, d, J=6.78 Hz), 4.33-4.27 (1H, m), 3.96 (3H, s), 3.93 (3H, s), 3.85(3H, s), 3.76 (2H, t, J=6.45 Hz), 3.68-3.62 (1H, m), 3.53 (1H, Dt,J=11.00, 5.41 Hz), 3.19 (1H, t, J=5.54 Hz)), 2.92-2.72 (4H, m).

Example 64(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 64 was prepared in an analogous fashion as described forexample 60, but starting from 3,4,5-trimethoxybenzaldehyde.

¹H NMR δ (ppm) (CHCl₃-d): 8.04 (1H, s), 7.57 (1H, d, J=7.92 Hz),7.40-7.32 (2H, m), 7.28-7.05 (6H, m), 6.96-6.91 (3H, m), 6.52 (1H, s)5.86 (1H, d, J=6.82 Hz), 4.38-4.30 (1H, m), 3.98-3.74 (10H, m),3.72-3.64 (1H, m), 3.57 (1H, d, J=10.07 Hz), 3.14 (1H, s), 2.94-2.76(4H, m).

Example 65(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide

Compound 65 was prepared in an analogous fashion as described forexample 60, but starting from 3,4,5-trimethoxybenzaldehyde.

¹H NMR δ (ppm) (CHCl₃-d): 8.04 (1H, s), 7.57 (1H, d, J=7.90 Hz), 7.36(1H, d, J=8.09 Hz), 7.13-6.97 (5H, m), 6.92 (1H, d, J=2.30 Hz), 6.52(1H, s), 6.73 (1H, d, J=6.83 Hz), 4.37-4.29 (1H, m), 3.90 (9H, s),3.84-3.66 (3H, m), 3.60 (1H, Dd, J=10.98, 5.95 Hz), 3.16 (1H, s),2.96-2.81 (4H, m)

Example 66(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide(a). tert-butyl 3,4-dimethoxyphenethylcarbamate

To a solution of compound 1a was added potassium carbonate (49.7 g).(Boc)₂O (52.3 g) was added dropwise in 1 hour. The reaction mixture wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated and water was added. The product was extracted into ethylacetate. The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel eluting with heptane and increasing amounts of ethylacetate to give the product as a pale solid.

Yield: 25 g

MS (ESI) m/z: 282 (M+H)⁺.

(b). tert-butyl 2-bromo-4,5-dimethoxyphenethylcarbamate

To a solution of compound 66a (1 g) in DCM (16 ml) and a aqueoussaturated NaHCO₃ solution (16 ml) was added dropwise bromine (0.75 g) at0° C. and stirred for another 1 hour. The reaction mixture was stirredfor an additional 2 hours at room temperature. A aqueous saturatedsodium thiosulfate solution was added and the product was extracted intoDCM. The organic phase was dried (MgSO₄), filtered and concentrated. Thecrude product was purified by chromatography on silica, eluting withheptane and increasing amounts of ethyl acetate to give the compound.

Yield: 1.22 g

¹H NMR δ (ppm) (CHCl₃-d): 6.98 (s, 1H), 6.71 (s, 1H), 4.53-4.62 (m, 1H),3.84 (s, 6H), 3.33 (t, 2H, J=7.2 Hz), 3.33 (t, 2H, J=7.2 Hz), 1.41 (d,9H, J=1.2 Hz).

(c). 2-(2-bromo-4,5-dimethoxyphenyl)ethanamine

To a solution of compound 66b (1.22 g) in DCM (2 ml) was added dropwise4N HCl/ethyl acetate (20 ml) and stirred for 1 hour at room temperature.The reaction mixture was concentrated, a saturated aqueous NaHCO₃solution was added and the product was extracted into ethyl acetate. Theorganic phase was dried over Na₂SO₄, filtered and concentrated to givethe crude product.

Yield: 0.8 g

¹H NMR δ (ppm) (DMSO-d): 7.50-8.20 (m, 3H), 7.10 (s, 1H), 6.92 (s, 1H),3.72 (s, 3H), 3.71 (s, 3H), 2.91-2.98 (m, 2H), 2.81-2.90 (m, 2H).

(d). (E)-ethyl 3-(3-fluorophenyl)-2-formamidoacrylate

To a suspension of sodium hydride (6 g) in THF (50 ml) was addeddropwise a solution of 3-fluorobenzaldehyde (6 g) and ethyliso-cyano-acetic ester (5 g) in THF (50 ml). The reaction was stirredfor 2 hours at room temperature. The reaction mixture was quenched witha aqueous saturated NH₄Cl solution and the aqueous layer was extractedwith ethyl acetate. The organic phase was dried over Na₂SO₄, filteredand concentrated. The crude product was purified by chromatography onsilica gel eluting with heptane and increasing amount of ethyl acetate.

Yield: 5 g

¹H NMR δ (ppm) (CHCl₃-d): 8.20-8.35 (m, 1H), 6.96-7.43 (m, 6H),4.30-4.40 (m, 2H), 1.37-1.42 (m, 3H).

(e). (Z)-ethyl 3-bromo-3-(3-fluorophenyl)-2-formamidoacrylate

A solution of compound 66d (5 g) and N-bromosuccinimide (4.5 g) incarbon tetrachloride (150 ml) was heated under reflux overnight. Thereaction mixture was concentrated and the residue was purified bychromatography on silica gel with heptane and increasing amounts ofethyl acetate.

Yield: 3.6 g

¹H NMR δ (ppm) (CHCl₃-d): 8.31 (s, 1H), 7.25-7.43 (m, 2H), 7.03-7.16 (m,3H), 4.05 (q, 2H, J=7.2 Hz), 0.98 (t, 3H, J=7.2 Hz).

(f). (Z)-ethyl 3-bromo-3-(3-fluorophenyl)-2-isocyanoacrylate

To a solution of compound 66e (5 g) in DCM (50 ml) was addedtriethylamine (3 eq). At 0° C. phosphorus oxychloride (12.2 g) was addeddropwise in 20 min. The reaction mixture was stirred at room temperaturefor 2 hours. The mixture was added dropwise to a potassium carbonate(120 g, 500 ml) solution in water and extracted with DCM. The organicphase was dried over Na₂SO₄, filtered and concentrated to give theproduct as a brown oil.

Yield: 3.5 g

MS (ESI) m/z: 298, 300 (M+H)⁺

(g). ethyl1-(2-bromo-4,5-dimethoxyphenethyl)-5-(3-fluorophenyl)-1H-imidazole-4-carboxylate

A solution of compound 66c and compound 69f in DMF was heated to 120° C.for 2 hours. The reaction mixture was concentrated, water was added andthe product was extracted into ethyl acetate. The organic phase wasdried over Na₂SO₄, filtered and concentrated to give the desiredproduct.

Yield: 114 mg

MS (ESI) m/z: 477, 479 (M+H)⁺

(h). ethyl3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxylate

To a solution of compound 66g (140 mg, crude) in dimethylacetamide (3ml) were added potassium carbonate (221 mg) andtetrakis(triphenylphosphine)palladium(0) (26 mg) under N₂. The reactionwas stirred at room temperature for 5 minutes. The reaction mixture washeated to 140° C. overnight. The solid was filtered off and the filtratewas concentrated. The crude product was used without purification in thenext step.

Yield 100 mg

MS (ESI) m/z: 395 (M+H)⁺

(i).3-(3-fluorophenyl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxylicacid

To a solution of compound 66h in THF/water (2 ml/2 ml) was added lithiumhydroxide (50 mg). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated, water was added andextracted with ethyl acetate. The aqueous layer was acidified withconcentrated HCl to pH=3 and then extracted with ethyl acetate. Theorganic phase was dried over Na₂SO₄, filtered and concentrated to givethe desired product.

Yield: 60 mg

MS (ESI) m/z: 369 (M+H)⁺

(j).(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

To a solution of compound 66i (60 mg, crude) in DMF (2 ml) were addedtryptophanol (50 mg), TBTU (20 mg) and triethylamine (0.5 ml). Thereaction mixture was stirred at rt for 30 minutes. The reaction mixturewas concentrated the residue was purified by preparative HPLC elutingwith acetonitrile and water to give the desired product.

Yield: 5 mg

MS (ESI) m/z: 541 (M+H)⁺

¹H NMR δ (ppm) (CH₃OH-d): 7.55-7.65 (m, 3H), 7.37-7.42 (m, 1H),7.21-7.37 (m, 3H), 7.08-7.12 (m, 2H), 6.95-7.08 (m, 2H), 4.32-4.42 (m,1H), 4.02 (t, 2H, J=7.6 Hz), 3.91-3.98 (m, 5H), 3.59-3.62 (m, 2H), 3.15(t, 2H, J=7.6 Hz), 2.97-3.11 (m, 2H)

Example 673-(2-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

Compound 67 was prepared in analogous fashion as described for example66.

MS (ESI) m/z: 541 (M+H)⁺

¹H NMR δ (ppm) (CH₃OH-d): 7.48-7.52 (m, 3H), 7.32-7.41 (m, 1H),7.21-7.40 (m, 3H), 7.03-7.11 (m, 2H), 6.89-6.97 (m, 2H), 4.30-4.38 (m,1H), 3.89-3.96 (m, 2H), 3.82-3.89 (m, 6H), 3.55-3.62 (m, 2H), 3.08 (t,2H, J=7.6 Hz), 2.92-3.05 (m, 2H)

Example 68N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

Compound 68 was prepared in analogous fashion as described for example66.

MS (ESI) m/z: 553 (M+H)⁺

¹H NMR δ (ppm) (CH₃OH-d): 7.45-7.57 (m, 2H), 7.11-7.32 (m, 4H),7.02-7.10 (m, 2H), 6.75-7.01 (m, 2H), 4.45-4.48 (m, 1H), 3.81-4.10 (m,8H), 3.72-3.85 (m, 3H), 3.45-3.60 (m, 2H), 3.08-3.18 (m, 2H), 2.92-3.05(d, 1H, J=9.6 Hz), 2.60-2.81 (d, 1H, J=7.2 Hz). 7.40-7.52 (m, 3H),7.19-7.42 (m, 1H), 6.99-7.15 (m, 3H), 6.82-6.98 (m, 4H), 4.24-4.40 (m,1H), 3.73-3.93 (m, 8H), 3.72 (s, 3H), 3.42-3.52 (m, 2H), 2.95 (dd, 1H,J=7.2, 14.4 Hz), 2.85 (dd, 1H, J=7.6, 15.6 Hz)

Example 69N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxypyridin-3-yl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide

Compound 69 was prepared in analogous fashion as described for example66.

MS (ESI) m/z: 554 (M+H)⁺

¹H NMR δ (ppm) (CH₃OH-d): 8.20-8.32 (m, 1H), 7.46-7.65 (m, 3H),7.17-7.37 (m, 1H), 6.85-7.05 (m, 5H), 4.27-4.48 (m, 1H), 3.75-4.02 (m,11H), 3.52-3.62 (m, 2H), 3.05 (d, 2H, J=7.6 Hz), 2.92-3.02 (m, 2H)

Example 70N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide(a). 2-chloro-3-methoxypyridine

To a solution of 2-chloro-pyridin-3-ol (100 g) in DMSO (1 L) was addedpotassium carbonate (320 g). Methyliodide was added dropwise. Thereaction mixture was heated to 50° C. overnight. The reaction mixturepoured into water and extracted with ethyl acetate. The organic phasewas washed with brine, dried over Na₂SO₄, filtered and concentrated togive the desired compound.

Yield: 110 g

(b). 2,3-dimethoxypyridine

To a solution of 2-chloro-3-methoxy-pyridine (110 g) in DMSO (1 L) wasadded sodium methoxide (124 g). The reaction mixture was heated to 80°C. overnight. The reaction mixture was poured into 3 L water andextracted with ethyl acetate. The organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated to give the crude product.

Yield: 105 g

¹H NMR δ (ppm) (CH₃OH-d): 7.70 (t, 1H, J=1.2 and 5.2 Hz), 7.01 (t, 1H,J=1.2 and 8.0 Hz), 6.81 (q, 1H, J=5.2 and 7.8 Hz), 4.00 (s, 3H), 3.85(s, 3H).

(c). 5-bromo-2,3-dimethoxypyridine

To a solution of 2,3-dimethoxy-pyridine (104 g) in DCM (1L) and asaturated aqueous solution of NaHCO₃ (1.6 ml) at 0° C. was added bromine(120 g). The reaction was stirred for 2 hours at 0° C. The reactionmixture was quenched with Na₂SO₃ (saturated in water, 500 ml) andstirred for 30 min. The aqueous layer was extracted with DCM, and theorganic phase was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography on silicagel with heptane and increasing amounts of ethyl acetate.

Yield: 100 g

¹H NMR δ (ppm) (CHCl₃-d): 7.70 (d, 1H, J=2.0 Hz), 7.06 (s, 1H, J=2.0Hz), 3.92 (s, 3H), 3.80 (s, 3H).

(d). 5,6-dimethoxynicotinaldehyde

To a solution of 5-Bromo-2,3-dimethoxy-pyridine (43 g) in THF (500 ml)at −78° C. was added n-butyllithium (191 mmol). After stirring for 30minutes at −78° C. DMF (28.8 g) was added dropwise and the reactionmixture was stirred at −78° C. for 2 hours. The reaction mixture wasquenched with NH₄Cl (saturated in water, 500 ml). The aqueous layer wasextracted with ethyl acetate, the organic phases were washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by chromatography on silica eluting with heptane withincreasing amounts of ethyl acetate.

Yield: 33 g

Compound 70 was further prepared in analogous fashion as described forcompound 60b and example 66.

MS (ESI) m/z: 554 (M+H)⁺

¹H NMR δ (ppm) (CH₃OH-d): 7.45-7.57 (m, 2H), 7.11-7.32 (m, 4H),7.02-7.10 (m, 2H), 6.75-7.01 (m, 2H), 4.45-4.48 (m, 1H), 3.81-4.10 (m,8H), 3.72-3.85 (m, 3H), 3.45-3.60 (m, 2H), 3.08-3.18 (m, 2H), 2.92-3.05(d, 1H, J=9.6 Hz), 2.60-2.81 (d, 1H, J=7.2 Hz).

Example 71N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide(a). 2,3-dimethoxy-5-vinylpyridine

To a stirred solution of compound 70c (30 g) in toluene (200 ml) wereadded Tetrakis(triphenylphosphine)palladium(0) (7.9 g) andtributyl(vinyl)stannane (66 g). The resulting mixture was heated to 110°C. overnight. The reaction was cooled and filtered, the filtrate wasconcentrated. The crude product was purified by chromatography on silicagel (petrol: ethyl acetate=20:1) to give the desired compound.

Yield: 11 g

¹H NMR δ (ppm) (CHCl₃-d): 7.685 (d, 1H, J=0.8 Hz), 7.152 (d, 1H, J=0.8Hz), 6.691-6.620 (m, 1H), 5.632 (d, 1H, J=8.8 Hz), 4.020 (s, 3H), 3.906(s, 3H).

(b). 2-(5,6-dimethoxypyridin-3-yl)ethanol

To a stirred solution of compound 71a (11 g) in THF (120 ml), was addedborane (20 ml, 10 mol/L). The mixture was heated under reflux for 2hours. The reaction mixture was cooled and sodium hydroxide (35.5 ml,15% in water) was added slowly to the mixture, followed by water (15.1ml, 30%). The resulting mixture was heated to 50° C. and stirred for 30minutes. Extracted with ethyl acetate, washed with brine dried overNa₂SO₄, filtered and concentrated. The crude product was purified bychromatography on silica gel (petrol:ethyl acetate=3:1) to give thedesired compound.

Yield: 3.6 g.

MS (ESI) m/z: 184 (M+H)⁺

(c). 2-(2-bromo-5,6-dimethoxypyridin-3-yl)ethanol

To a solution of compound 71b (3.6 g) in DCM (30 ml) and a aqueoussaturated NaHCO₃ solution (30 ml) at 0° C. was added dropwise bromine(1.32 ml,). The reaction was stirred for 1 hour at 0° C. and then warmedto room temperature for additional 1 hour. The reaction mixture wasquenched with saturated sodium thiosulfate (saturated in water 100 ml).The aqueous layer was extracted with DCM. The organic phase was dried(MgSO₄), filtered and concentrated to give the desired compound.

Yield: 4.1 g

MS (ESI) m/z: 262, 264 (M+H)⁺

(d). methyl 1H-pyrrole-3-carboxylate

To a solution of potassium-tert-butoxide (105 g) in THF (1.2 L) wasadded dropwise a solution of methyl acrylate (66 g) andtoluenesulfonylmethyl isocyanide (150 g) in THF (300 ml). The resultingmixture was stirred at room temperature for 2 h. The reaction wasquenched with water and extracted with ethyl acetate. The organic phasewas dried (MgSO₄), filtered and concentrated. The crude product waspurified by chromatography on silica gel (Petrol:ethyl acetate=5:1) togive the desired compound.

Yield: 40 gram

¹H NMR δ (ppm) (CHCl₃-d): 8.815 (br, 1H), 7.404 (s, 1H), 6.729 (d, 1H,J=1.2 Hz), 6.621 (d, 1H, J=0.4 Hz), 3.788 (s, 3H).

(e) methyl 5-bromo-1H-pyrrole-3-carboxylate

To a solution of compound 71d (40 g) in THF (60 ml) was addedN-bromosuccinimide (67.6 g) portion wise at −78° C. The reaction mixturewas allowed to stir at room temperature overnight. The reaction mixturewas concentrated. The crude product was purified by chromatography onsilica gel, eluting with (Petrol:ethyl acetate=10:1) to give the desiredcompound.

Yield: 38 g

¹H NMR δ (ppm) (CHCl₃-d): 8.625 (br, 1H), 7.364 (dd, 1H, J₁=2.0 HzJ₂=2.8 Hz), 6.588 (dd, 1H, J₁=2.0 Hz J₂=2.4 Hz), 3.808 (s, 3H).

(f) methyl5-bromo-1-(2-(2-bromo-5,6-dimethoxypyridin-3-yl)ethyl)-1H-pyrrole-3-carboxylate

To a solution of compound 71c (3.1 g) in THF (60 ml) were addedtriphenylphosphine (3.72 g), DIAD (2.81 ml), DIPEA (2.35 ml) andcompound 71e (2.35 ml). The resulting mixture was heated under refluxfor 2 hours. The reaction mixture was cooled and filtered, the filtratewas concentrated. The crude product was purified by columnchromatography on silica gel eluting with (Petrol:ethyl acetate=10:1) togive the desired compound.

Yield: 4 g

¹H NMR δ (ppm) (CHCl₃-d): 7.170 (s, 1H), 6.567 (d, 1H, J=1.2 Hz),6.367-6.191 (m, 1H), 4.177-4.100 (m, 2H), 3.989 (s, 3H), 3.759 (s, 3H),3.666 (s, 3H), 3.043 (t, 2H, J=6.8 Hz).

(g) methyl2,3-dimethoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-9-carboxylate

To a solution of compound 71f (3.5 g, crude) in toluene (50 ml) wereadded Pd(PPh₃)₂Cl₂ (160 mg) and (n-Bu₃Sn)₂ (2.5 ml). The resultingmixture was heated to 120° C. overnight. The reaction was cooled andfiltered, the filtrate was concentrated. The crude product was purifiedby column chromatography on silica gel, eluting with (Petrol:ethylacetate=10:1) to give the desired compound.

Yield: 300 mg

MS (ESI) m/z: 289 (M+H)⁺

(h) methyl8-(3-fluorophenyl)-2,3-dimethoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-9-carboxylate

To a solution of compound 71g (60 mg) in dioxane (5 ml) were addedtriphenylphosphine (10 mg), Palladium(II)acetate (5 mg),1-fluoro-3-iodo-benzene (93 mg) and cesium carbonate (137 mg). Theresulting mixture was heated to 120° C. overnight. The reaction wascooled and filtered and the filtrate was concentrated. The crude productwas purified by preparative HPLC, eluting with acetonitrile and water togive the desired compound.

Yield: 25 mg

MS (ESI) m/z: 383 (M+H)⁺

(i)8-(3-fluorophenyl)-2,3-dimethoxy-5,6-dihydropyrrolo[1,2-h][1,7]naphthyridine-9-carboxylicacid

To a solution of compound 71h (25 mg) in methanol (1 ml), water (1 ml)and THF (1 ml), was added potassium hydroxide (73 mg). The reactionmixture was heated to 60° C. overnight. The mixture was concentrated andwater was added. The mixture was acidified by concentrated HCl to pH=2and extracted with DCM. The organic phase was dried (MgSO₄), filteredand concentrated to give the desired compound.

Yield: 29 mg

MS (ESI) m/z: 369 (M+H)⁺ ₁₀

(j).N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide

To a solution of compound 71i in DCM were added compound tryptophanol(50 mg, TBTU (20 mg) and triethylamine (0.5 ml). The reaction wasstirred at room temperature for 30 min. The reaction mixture waspurified by preparative HPLC, eluting with acetonitrile and water togive the desired compound.

Yield: 8 mg

MS (ESI) m/z: 541 (M+H)⁺

¹H NMR δ (ppm) (CHCl3-d): 7.998 (s, 1H), 7.564 (d, 1H, J=4.0 Hz), 7.361(d, 1H, J=4.0 Hz), 7.222 (t, 1H, J=2.0 Hz), 7.198-7.119 (m, 1H),7.053-7.011 (m, 4H), 6.931 (s, 1H), 6.857 (s, 1H), 5.860 (d, 1H, J=2.8Hz), 4.359-4.327 (m, 1H), 4.075 (s, 3H), 3.879 (s, 3H), 3.817 (t, 2H,J=6.8 Hz), 3.727-3.611 (m, 2H), 2.997-2.859 (m, 5H).

Example 72 Antagonistic Activity of Compounds at the Human FSH ReceptorExpressed in CHO Cells

Antagonistic activity of the compounds at the human FSH receptor wasdetermined in Chinese Hamster Ovary (CHO) cells stably transfected withthe human FSH receptor and cotransfected with a cAMP responsive element(CRE)/promotor directing the expression of a firefly luciferase reportergene. Binding of the compounds to the Gs protein-coupled FSH receptorwill result in an increase of cAMP, which in turn will induce anincreased transactivation of the luciferase reporter. The cells (7,500cells/well of a 384 well plate) were incubated in Dulbecco' minimalessential F12 modified medium (Invitrogen), supplemented with 1 μg/mlbovine insulin, 5 μg/ml human apo-transferrin, 100 μml penicillin G and100 μg/ml streptomycin with the test compounds (concentration between0.316 nM and 10.0 μM) in duplicate together with 49 pM recFSH (which, atthis concentration in the absence of test compound, induces 80% of themaximal luciferase stimulation) in a humidified atmosphere (95%) at 5-7%CO₂ and 37° C. The final concentration of DMSO was 1%. After 4 hours ofincubation, plates were allowed to adjust to room temperature for 1hour. Then, SteadyLite (Perkin Elmer) solution was added to the wellsand cells were allowed to lyse for at least 1 hour at room temperature.Subsequently, luciferase activity was measured in a luminescencecounter. The signal is expressed as counts per second (cps). The IC50(concentration of test compound causing half-maximal (50%) inhibition ofthe maximally attainable inhibition of the luciferase stimulation by thecompound) and efficacy of the compounds were determined using thesoftware program MathIQ (version 2.3, ID Business Solutions Limited).

The compounds of all examples have an IC50 of 10⁻⁵ M or lower. Thecompounds of examples 1-4,9,15,30-32, 39, 46-48, 51 and 66-68 have anIC50 of less than 10⁻⁶ M and more than 10⁻⁷ M. The compounds of examples5-8, 10-14, 16-19, 22-29, 33-38, 40-45, 49, 50, 52-65 and 70 have anIC50 of less than 10⁻⁷ M.

Example 73 Functional Assay for Assessing hFSHR Antagonistic Activity ofTest Compounds in Human Granulosa Cell Cultures

Human granulosa cells were obtained in the course of follicularaspiration for retrieval of matured oocytes during routine IVFprocedures approximately 36 hours after hCG administration to thepatient. Follicular fluid was collected as one batch per patient andafter oocyte removal centrifuged for 5 minutes at 350 g at roomtemperature (RT). The pellet was resuspended in 5 ml collagenase (0.1%)containing isolation medium, layered on 5 ml of Histopaque-1077 andcentrifuged (450 g for 20 minutes, RT) to separate the granulosa cellsfrom the erythrocytes. The granulosa cells and other mononuclear cells(e.g. lymphocytes) were obtained from the interface and washed once withisolation medium (450 g, 20 minutes). After aspiration of thesupernatant, the pellet was resuspended in isolation medium andtransported from the hospital to the laboratory. The granulosa cells arepelleted by centrifugation (350 g, 5 minutes) and resuspended in a smallvolume of culture medium with 10% fetal calf serum (FCS). To facilitatecell dispersal the suspension was subjected to gentle mechanicaldissociation.

Cell viability was determined by Trypan Blue exclusion and the granulosacells were plated at a density of 25.000 viable cells/200 μl/well inculture medium with 10% FCS in collagen coated 96-wells plates, andcultured at 37° C. under a humidified atmosphere supplemented with 5%CO₂. Every 72 hours the cells are washed once with pre-warmed culturemedium to remove dead cells, debris and non-adherent cells. Seven daysafter the start of the culture, the cells are washed again with culturemedium. Medium was aspirated and 250 μL isolation medium withisobutylmethylxanthine (IBMX) with human recombinant FSH (hrecFSH: 0 and250 mU/mL) or with hrecFSH (250 mU/mL) in combination with test compoundof example 5 was incubated for an additional 48 hours at 37° C., 5% CO₂.All test conditions were performed in triplicate. Subsequently,supernatant was collected in 96 well plates. Finally 25 μL supernatantwas transferred to a new 96 deep-well plate and used for thedetermination of cAMP levels with the cAMP EIA kit (Amersham LifeSciences, cat. no RPN 225). Immediately after aspiration of thesupernatant of the granulosa cells, 150 μL culture medium supplementedwith 10 μM testosterone, was added to the wells. After 2 hours ofincubation at 37° C., 5% CO₂, the supernatant was collected and used forthe determination of estradiol levels with an estradiol-ELISA (DRGinstruments, art. no. EIA-2693). Supernatants were diluted 1:300 inDulbecco's phosphate buffered saline (DPBS, Hyclone Cat. No. SH30028.03)and a self-made calibration curve of estradiol in DPBS was used for thedetermination of estradiol levels in the supernatants.

1. A compound according to Formula I

or a pharmaceutically acceptable salt thereof, wherein X is C(R10) or N;Y is C(R1) or N; R1 is H, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl;R3 is phenyl, (2-8C)heteroaryl, benzoyl, (2-8C)heteroarylcarbonyl, thephenyl or heteroaryl moieties of which may optionally be substitutedwith one or more substituents selected from R11, or R3 is (1-6C)alkyl,(2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (1-6C)alkylcarbonyl,(2-6C)alkenylcarbonyl, (2-6C)alkynylcarbonyl or(3-6C)cycloalkylcarbonyl; R7 and R8 are independently H or (1-4C)alkoxy;R9 is hydroxy or H, or R9 is (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,(1-4C)alkoxy, (2-4C)alkenoxy, (3-6C)cycloalkyl, (3-6)cycloalkoxy,(3-6C)cycloalkyl(1-4C)alkoxy, (2-6C)heterocycloalkylcarbonyl,(di)[1-4C]alkylaminocarbonyl, (2-6C)heterocycloalkyl, the alkyl or(hetero)cycloalkyl moieties of which may optionally be substituted withone or more substituents selected from R12 or, R9 is (2-8C)heteroaryl,phenyl, phenyl(1-4C)alkoxy, (2-8C)heteroaryl(1-4C)alkoxy, the phenyl orheteroaryl moieties of which may optionally be substituted with one ormore substituents selected from R16; R10 is H or (1-4C)alkoxy; R11 ishydroxy, amino, halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl,(1-4C)alkoxy or (di)[1-4C)alkyl]amino; R12 is hydroxy, amino, halogen,cyano, (1-4C)alkoxy or (di)[1-4C)alkyl]amino; R13 and R14 areindependently H or (1-3C)alkyl; R15 is H, (1-3C)alkyl, or R14 and R15may be joined in a (3-6C)cycloalkyl ring; and R16 is hydroxy, amino,halogen, nitro, trifluoromethyl, cyano, (1-4C)alkyl, (1-4C)alkoxy or(di)[1-4C)alkyl]amino.
 2. The compound according to claim 1 wherein R1is H or (1-4C)alkyl; R8 is (1-4C)alkoxy; R9 is hydroxy or R9 is(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy, (2-4C)alkenoxy,(3-6)cycloalkoxy, (3-6C)cycloalkyl(1-4C)alkoxy,(2-6C)heterocycloalkylcarbonyl, (di)[1-4C]alkylaminocarbonyl, the alkylor (hetero)cycloalkyl moieties of which may optionally be substitutedwith one or more substituents selected from R12 or, R9 is(2-8C)heteroaryl, phenyl(1-4C)alkoxy, the phenyl or heteroaryl moietiesof which may optionally be substituted with one or more substituentsselected from R16;
 3. The compound according to claim 2 wherein Y isC(R1).
 4. The compounds according to claim 3 wherein R1 is H.
 5. Thecompound according to claim 4 wherein R13, R14 and R15 are H.
 6. Thecompound according to claim 1 wherein R9 is (1-6C)alkyl, (1-4C)alkoxy or(3-6C)cycloalkyl(1-4C)alkoxy, the alkyl moieties of which may optionallybe substituted with one or more substituents selected from R12; or R9 is(2-8C)heteroaryl or phenyl(1-4C)alkoxy, the phenyl or heteroarylmoieties of which may optionally be substituted with one or moresubstituents selected from R16.
 7. The compound according to claim 6wherein R3 is phenyl, (2-8C)-heteroaryl, benzoyl,(2-8C)heteroarylcarbonyl, the phenyl or heteroaryl moieties of which mayoptionally be substituted with one or more substituents selected fromR11, or R3 is (1-6C)alkyl, (2-6C)alkenyl, (1-6C)alkylcarbonyl or(3-6C)cycloalkylcarbonyl.
 8. The compound according to claim 7 whereinR3 is phenyl or (2-8C)heteroaryl, both optionally substituted with oneor more substituents selected from R11.
 9. The compound according toclaim 8 wherein X is C(R10).
 10. The compound according to claim 1selected from the group of(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-1-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;N-(1-hydroxy-3-(1H-indol-3-yl)-2-methylpropan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;N-(1-(1-(1H-indol-3-yl)cyclopropyl)-2-hydroxyethyl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3,5-dimethylphenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide:(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(4-nitrophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(methylamino)-3-(pyridin-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(3-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(4-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-m-tolyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(6-aminopyridin-3-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-chlorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-(4-hydroxyphenyl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;3-(2-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(furan-2-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-cyanophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(3-(trifluoromethyl)phenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide,(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-3-isobutyryl-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-pivaloyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-butyryl-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(cyclopropanecarbonyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-3-(thiophene-2-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-benzoyl-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-isopropoxy-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-diisopropoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-9-hydroxy-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-(allyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxyethoxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-(benzyloxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-(cyclopentylmethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-(cyclopropylmethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;3-(3-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pentan-2-yloxy)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-9-(2-hydroxyethoxy)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-(2-(dimethylamino)ethoxy)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;9-(2,3-dihydroxypropoxy)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;9-(2,3-dihydroxypropoxy)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-ethyl-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;3-(3-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(3-methylbutan-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methylprop-1-enyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(3-methylbut-2-en-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(morpholine-4-carbonyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N2-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-N9,N9-dimethyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2,9-dicarboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(pyrimidin-5-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-(2-(dimethylamino)pyrimidin-5-yl)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1-methyl-1H-pyrazol-4-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;3-(3-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-3-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-3-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1-methyl-1H-pyrazol-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-9-(2-(dimethylamino)pyrimidin-5-yl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(2-methoxypyridin-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(6-methoxypyridin-3-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8-methoxy-9-(1H-pyrazol-4-yl)-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-7,8,9-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)—N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9,10-trimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-2-carboxamide;(R)-3-(3-fluorophenyl)-N-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide;3-(2-fluorophenyl)-N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide;N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide;N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxypyridin-3-yl)-5,6-dihydroimidazo[2,1-a]isoquinoline-2-carboxamide;N—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide;orN—((R)-1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)-8,9-dimethoxy-3-(2-methoxyphenyl)-5,6-dihydroimidazo[1,2-h][1,7]naphthyridine-2-carboxamide.11. (canceled)
 12. (canceled)
 13. A pharmaceutical composition whichcomprises a compound of formula I according to claim 1 or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.
 14. A pharmaceutical compositionaccording to claim 13, which further comprises at least one additionaltherapeutically active agent.
 15. A method of treating endometriosis,pre-menopausal and peri-menopausal hormone-dependent breast cancer,uterine fibroids, or other menstrual-related disorders, comprisingadministering a compound according to claim
 1. 16. A method ofcontraception comprising administering a compound according to claim 1.